Enhancing The Therapeutic Efficacy of Nanoparticles For Cancer Treatment Using Versatile Targeted Strategies

Tian et al.
Journal of Hematology & Oncology (2022) 15:132

https://doi.org/10.1186/s13045-022-01320-5
REVIEW Open Access
Enhancing the therapeutic efficacy

of nanoparticles for cancer treatment using
versatile targeted strategies
Hailong Tian1,2†, Tingting Zhang1,2†, Siyuan Qin2, Zhao Huang2, Li Zhou2, Jiayan Shi3, Edouard C. Nice4,
Na Xie1,2,4*, Canhua Huang1,2* and Zhisen Shen1*
Abstract
Poor targeting of therapeutics leading to severe adverse effects on normal tissues is considered one of the obstacles
in cancer therapy. To help overcome this, nanoscale drug delivery systems have provided an alternative avenue for
improving the therapeutic potential of various agents and bioactive molecules through the enhanced permeability
and retention (EPR) effect. Nanosystems with cancer-targeted ligands can achieve effective delivery to the tumor cells
utilizing cell surface-specific receptors, the tumor vasculature and antigens with high accuracy and affinity. Addition-
ally, stimuli-responsive nanoplatforms have also been considered as a promising and effective targeting strategy
against tumors, as these nanoplatforms maintain their stealth feature under normal conditions, but upon homing in
on cancerous lesions or their microenvironment, are responsive and release their cargoes. In this review, we compre-
hensively summarize the field of active targeting drug delivery systems and a number of stimuli-responsive release
studies in the context of emerging nanoplatform development, and also discuss how this knowledge can contribute
to further improvements in clinical practice.
Keywords: Drug delivery, Targeted strategies, Active targeting, Stimuli-responsive materials, Cancer treatment
Background an urgent need for site-specific delivery of therapeutic

Cancer is one of the leading causes of death worldwide, agents to the tumor region. For this reason, nanotech-
and despite the current arsenal of anticancer strategies, nology-based formulations have been the focus of a large
the number of patients is continuously increasing [1, 2]. body of research as effective approaches for overcoming
Statistics have shown that one in 6 women and one in 5 the bottlenecks of undirected biodistribution, undesired
men worldwide develop a tumor in their lifetime [3, 4] side effects and high-dose administration [7].
which accounts for nearly 1 in 6 deaths. The main rea- With the increased uptake in nanomedicine, various
son behind the poor treatment efficacy is the low target- versatile nanoformulations with excellent biocompat-
ing ratio of therapeutics which can also induce severe ibility and pharmacokinetic properties, such as micelles,
side effects on healthy tissues [5, 6]. Therefore, there is liposomes, nanoparticles, and nanoemulsions, have
exhibited great potential for the delivery of novel anti-
cancer drugs (Fig. 1) [8–10]. These nanoparticles can
†
Hailong Tian and Tingting Zhang contributed equally to this work effectively address the poor water solubility and unde-
*Correspondence: [email protected]; [email protected]; [email protected] sired adverse effects often observed during the delivery
1
Department of Otorhinolaryngology and Head and Neck Surgery, The of therapeutic agents and prolong their blood circulation
Affiliated Lihuili Hospital, Ningbo University, 315040 Ningbo, Zhejiang, China time for enhanced tumor accumulation, thereby mark-
Full list of author information is available at the end of the article
edly facilitating their use as therapeutic agents for tumor
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Tian et al. Journal of Hematology & Oncology (2022) 15:132 Page 2 of 40
nanoparticles also overcome many of the disadvantages

of conventional nanoagents by site-specific tumor tar-
geting and controlled drug release, such as providing
improved therapeutic agent delivery, overcoming the off-
target side effects and enhancing the therapeutic benefits.
For these reasons, smart targeting nanoparticles for
efficient tumor accumulation and controlled release
of therapeutic agents are gaining widespread attention
as personalized treatment regimens [23]. This review
focuses on important recent advances in versatile target-
ing strategies for tumor treatment, including receptor-
mediated and stimuli-responsive targeting nanoparticles,
which present exceptional potential as multimodal deliv-
ery platforms against cancer. Special emphasis has been
given to stimuli-responsive nanoparticles as novel tar-
geting strategies and their potential to support paradigm
changes in cancer treatment. Furthermore, the current
challenges and future prospects of receptor-mediated
and stimuli-responsive targeting nanoparticles are also
Fig. 1 The main drug delivery systems in tumor treatment
discussed.
Receptor‑mediated active targeting strategy

therapies [10–12]. Importantly, these novel nanomedi-
Nanoparticles can be used to overcome the TME barri-
cines generated by encapsulating specific therapeutic
ers and deliver pharmaceutical active ingredients to the
agents in nanocarriers can achieve satisfactory tumor
tumor sites by either passive or active targeting strategies
targeting by utilizing the EPR effect-mediated pas-
(Fig. 2). Passive targeting involves the transport of nano-
sive targeting strategy [13, 14]. Furthermore, active tar-
particles through the leaky tumor vasculature-mediated
geting can also be effectively achieved by conjugating
EPR effect, leading to nonspecific tumor accumula-
nanomedicines with ligands that can specifically target
tion. In active targeting strategies, specialized chemical
overexpressed receptors on the tumor cells [15–17]. The
moieties or ligands can be conjugated to the surface of
inclusion of active targeting ligands over the surface of
nanoparticles and are capable of site-specific delivery to
nanoparticles improves their targeting toward tumor
tumor sites. Generally, these ligands are chosen based
cells (on-targets) rather than healthy cells (off-targets).
upon expression levels of specific receptors and their
Therefore, this feature of ligands not only increases the
internalization at the target site. It should be noted that
therapeutic index but also minimizes the associated side
these receptors or cell surface markers should be overex-
effects.
pressed on target cells, facilitating the homing action of
Recently, stimuli-responsive nanoparticles have also
nanoparticles. Additionally, stimuli-responsive nanopar-
been proposed as a promising active targeting strategy
ticles have also been considered a promising active tar-
for tumor treatment [18–22]. Specifically, an acidic envi-
geting strategy for tumor treatment, as they enable the
ronment, high levels of reactive oxygen species (ROS)
safe delivery of the agents while controlling their release
and glutathione (GSH), and overexpression of specific
at the target sites.
enzymes in the tumor microenvironment (TME) can
A number of receptors are overexpressed on the tumor
contribute to the development of stimuli-responsive
cell surface, which enables them to be distinguished from
nanoparticles for targeted drug delivery, as these nano-
healthy cells at the molecular level. Moreover, the pro-
particles maintain their stealth features in the normal
gressive use of tumor proteomics and bioinformatics has
physiological environment but upon homing to targeted
contributed significantly to the discovery of these specific
sites or the local microenvironment are responsive and
receptors [24]. The addition of specific ligands on the
release encapsulated agents [18–21]. Moreover, func-
nanoplatform surfaces allows them to selectively target
tionalized nanoparticles can also be activated by external
tumor cells. Once bound to specific receptors, the encap-
stimuli including magnetic fields, light, and ultrasound,
sulated therapeutic agent nanoplatform can be effectively
to realize efficient tumor accumulation and controlled
taken up into tumor cells through receptor-dependent
drug release in a temporal and spatial-specific fashion
endocytosis (Fig. 3). Therefore, strategies for targeting
[22]. It should be noted that these stimuli-responsive
drugs to tumor cell surface receptors to enhance tumor
Fig. 2 Schematic representation of receptor-mediated active targeting and passive targeting through the EPR effect
accumulation have attracted extensive attention in recent agents in clinical use are monoclonal antibodies (mAbs)
years. Table 1 summarizes some of the specific receptors and small molecule tyrosine kinase inhibitors (TKIs).
overexpressed on various tumor cells along with their The mAbs can be directly applied to deliver therapeu-
related ligands. Utilizing cell surface active targeting tic agents to tumor cells through drug-Ab complexes or
strategies has greatly advanced tumor treatment. Some modified on the surface of the nanoplatform-loaded ther-
of these approaches are summarized in the following apeutic agents [29, 30].
sections. Recently, EGFR-based nanoplatforms have been widely
explored against cancers [31–35]. These nanoparticles
Epidermal growth factor receptor (EGFRs)‑based active are generally internalized into the cells through an EGFR-
targeting mediated endocytosis process, resulting in the formation
The EGFR, a transmembrane protein, is involved in the of lysosomes and release of encapsulated drugs for cancer
occurrence of several types of cancers, including lung, treatment. As an exemplar, Nan and co-workers prepared
pancreatic, colorectal, and breast cancers [24]. Activation versatile nanoplatforms capable of specific codeliv-
of the EGFR is triggered by the binding of ligands, includ- ery of DOX and cisplatin to tumor sites by utilizing an
ing EGF, transforming growth factor-α (TGF-α), epireg- EGFR-targeted approach [33]. These targeted nanopar-
ulin, heparin-binding EGF, betacellulin, amphiregulin, ticles showed high stability with sustained cargo release,
and neuregulin G2β. This enables protein kinase (PK) to showing satisfactory killing effects in lung cancer mod-
transfer a phosphate molecule from adenosine triphos- els. In a similar approach, Liang et al. prepared versatile
phate (ATP) to the tyrosine residues, resulting in phos- nanoplatforms functionalized with anti-EGFR Ab for
phorylation of the intracellular domain, which mediates lesion-specific delivery of carmustine to malignant glio-
a signaling cascade pathway [25, 26]. Eventually, this pro- blastomas for growth suppression [34]. Confirming the
cess can result in tumorigenesis and cancer progression, role of the EGFR, Shuai and co-workers reported higher
thereby making EGFR one of the main anticancer tar- internalization of an anti-EGFR monoclonal antibody-
gets [27, 28]. The most commonly used EGFR targeting conjugated nanoplatform in EGFR-positive human skin
Fig. 3 Schematic representation of receptor-mediated endocytosis
Table 1 The overexpressed receptors on various tumor cells and their ligands
Receptor Ligands Tumor Refs.
Folate Folic acid Breast, lung, cervical cancer, hepatocellular carcinoma [414–419]
CD14 anti-CD14 mAb Prostatic cancer [420]
CD22 anti-CD22 mAb Lymphoma cancer [421, 422]
CD44 HA, chondroitin sulfate Breast, Melanoma [423–426]
αvβ3 integrin RGD peptide Endothelial, glioma, lung, melanoma, breast cancer [427–434]
Transferrin TfR ligand, transferrin Breast cancer, Glioblastoma [435–438]
HER2 Trastuzumab Breast anti-HER2 scFv neu peptide (FCDG- Breast cancer [439–441]
FYACYADV) KCCYSL (P6.1 peptide)
Estrogen Estrone, 17 β-Estradiol, tamoxifen Breast cancer [442–446]
Chemokine (CXCR4) LFC131 peptide, anti-CXCR4 mAb, Peptide R, Peptide Breast, lung cancer, hepatocellular carcinoma, Lym- [447–454]
T22 phoma
LHRH Peptide Breast cancer [106, 107]
Biotin Biotin Breast, lung, cervical cancer, hepatocellular carcinoma [455–460]
PSMA A10 PSMA Apt, anti-PSMA Prostatic cancer [461–463]
VEGF anti-VEGF mAb Pancreatic cancer [464, 465]
IL4 AP1 peptide Colon, glioblastoma [466–468]
IL4 Pep-1 Lung cancer [469–471]
IL13 IL13 peptide Glioblastoma [472–474]
Asialoglycoprotein Lactobionic acid, galactose Hepatocellular carcinoma [475, 476]
receptor (ASGPR)
squamous cell carcinoma compared to EGFR-negative gemcitabine (Gem) encapsulated nanoplatforms could
breast cancer [35]. Furthermore, Choi and co-work- effectively inhibit tumor growth [36]. Gupta and col-
ers demonstrated that binding EGFR-targeting Abs to leagues constructed a Gem encapsulated nanoplatform
against pancreatic cancer through covalent binding to targeted delivery of epirubicin to overexpressed αvβ3
EGFR antibodies [37], presenting higher cytotoxicity of integrin in esophageal cancer, resulting in the designed
the designed nanoplatform for EGFR-overexpressing nanoplatforms not only reducing epirubicin-induced
pancreatic cell lines. Moreover, anti-EGFR functionalized cardiotoxicity but also improving the therapeutic effect
Fe2O3 nanoparticles can be used as magnetic resonance in comparison to free agents [52]. Recently, Roy et al.
imaging contrast agents for tumor diagnosis [38, 39]. In prepared pH-responsive nanoparticles for the effec-
an interesting review article, Yi and colleagues discussed tive delivery of raloxifene to breast cancer cells through
the role of EGFR tyrosine kinase inhibitors in targeted RGD-modified nanocarriers. The designed nanoparticles
nanoplatforms for tumor treatment [40]. showed good cytotoxicity and antitumor efficacy toward
Supported by the rapid advancement of nanomedi- αvβ3 positive breast cancer cells and a 4T1-bearing
cine, these inhibitor-loaded nanoparticles are showing mouse model [53]. In another recent study, Wang’s group
improved bioavailability, prolonged blood circulation, reported a bispecific assembling peptide antiCD3-G7-
enhanced tumor accumulation and reduced off-tar- RGD for tumor immunotherapy [54]. The RGD was used
get side effects, leading to significant augmentation of to improve tumor accumulation and cell internalization
therapeutic efficacy [41, 42] supporting their continued via the integrin receptor-mediated endocytosis process.
development. The anti-CD3 was designed to target the CD3 receptor
on T lymphocytes and induce a T cell-mediated immune
αvβ3 integrin receptor‑mediated active targeting response against tumor cells overexpressing integrin
Integrin receptors, consisting primarily of transmem- αvβ3, resulting in satisfactory antitumor effects. In sum-
brane glycoproteins, can mediate cell–cell and cell- mary, nanoparticles can preferentially and effectively tar-
extracellular matrix adhesion [43]. More than 23 integrin get integrin binding sites in tumors (e.g., the RGD motif ),
heterodimers have been identified in humans to date thereby providing a solid basis for developing precision
[44]. These receptors control the connection between the tumor treatment strategies [55].
extracellular matrix (ECM) and the cell cytoskeleton as
well as maintaining communications between cells [43, Folate receptor (FR)‑mediated active targeting
45]. The extracellular domains of integrins have strong FRs, a class of glycoproteins, have been classified into
affinity for the proteins (collagen, fibronectin, laminin three subtypes namely FRα, FRβ and FRγ. It should be
and vitronectin) in the ECM. Furthermore, integrins noted that FRα and FRβ can closely bind to the tumor
can play a significant part in several signaling pathways cell membrane via a glycosylphosphatidylinositol anchor,
involved in cell proliferation after combining with the while FRγ has only been reported in hematopoietic cells
ECM [46]. It is possible to target integrin receptor-pos- [4, 56–58]. Among them, FRα is the most widely gener-
itive tumor cells through functionalized nanoparticles ated FR subtype and is overgenerated in various tumor
containing an integrin targeting motif (such as RGD- cells, especially in breast, lung, kidney, cervical, and ovar-
containing peptides and polymers). This approach has ian cancer [59–61]. Moreover, FR can transport folate
been extensively explored [47–53]. For example, Lu and into tumor cells via the receptor-mediated endocytosis
co-workers prepared cyclic RGD peptide-functionalized process [62]. For this reason, a number of FA-based nan-
nanoplatforms for paclitaxel (PTX) delivery to glio- oplatforms have been prepared for increased internaliza-
blastoma cells overexpressing αvβ3, resulting in antitu- tion of therapeutic agents by tumor cells [63–65]. In one
mor effects in in vivo models [49]. In another example, example, Murgia et al. prepared an organic/inorganic
Li et al. prepared RGD-conjugated resveratrol loaded hybrid nanoplatform modified by FA-chitosan conju-
human serum albumin nanoparticles, which showed gates to load upconverting NaYF4 nanoparticles and dau-
higher internalization efficiency (approximately 3.6-fold norubicin for tumor therapy [62]. The FA modification
higher) as well as improved tumor suppression features significantly improved the cellular uptake of the nano-
compared to the non-functionalized formulation [50]. particles, and an in vivo xenograft model also showed a
Amreddy and co-workers developed RGD-functional- positive antitumor effect. In another example, Wang et al.
ized nanoparticles for the delivery of therapeutic agents designed an FA-conjugated chitosan loaded rutin pre-
(PTX and cisplatin) to αvβ3 integrin receptor-over- pared palladium nanoplatform for FA-mediated target-
expressing lung cancer cells and found that the RGD- ing treatment. The introduction of FA into the designed
targeted nanoformulations showed higher endocytosis nanoplatform significantly improved the endocytosis
efficiency (approximately 1.4-fold higher) compared with efficiency of the nanoparticles in breast cancer cells. The
non-RGD-functionalized formulations [51]. Pan and designed nanoplatform was shown to considerably sup-
co-workers developed RGD-modified fluorescent nano- press cell proliferation as evidenced by a cell viability
platforms for simultaneous fluorescence-guided and assay [66]. Mechanistically, FRs can identify and bind to
extracellular FA-modified nanoparticles and then trans- integrated as targeting units on nanoparticles against
port them into the tumor cells through a FR-mediated HER2 overexpressing cancer. The introduction of trastu-
endocytosis process [67]. In these nanoparticles, the FA zumab (TZ), a humanized anti-HER2 Ab, endows nano-
portion is used as a tumor-targeting ligand. On bind- particles with excellent therapeutic efficacy for breast
ing to the FR on tumor cells, the cell membrane can cancer treatment [81]. It can block cell cycle arrest and
invaginate and pinch off to form endosomes which sub- reduce angiogenesis by disturbing downstream HER2
sequently reach lysosomes or other organelles. The drug- signaling activity. The interaction between TZ and HER
encapsulated nanoparticles can dissociate from the FR blocks receptor cleavage and activates the response of
and effectively release the encapsulated drug at the TME Ab-dependent cellular cytotoxicity and receptor degrada-
for tumor treatment. tion following internalization of the TZ-HER2 complex.
Pertuzumab (PZ), another humanized mAb, has been
Transferrin (Tf) receptor‑mediated active targeting used to suppress heregulin-mediated activation of HER2
e3+ pool in the body, Tf plays an impor-
As the critical F phosphorylation and tumor proliferation [82]. Nanopar-
tant role in Fe metabolism and delivery. To meet the ticles functionalized with anti-HER2 Abs or its fragments
growing requirements of Fe for maintaining cell growth can be effectively used for specific delivery of therapeu-
and division, transferrin receptors (TfR) are frequently tic agents to HER2-overexpressed tumor cells by the
overexpressed on the surface of a number of tumors HER2 receptor-mediated endocytosis process [83] which
including pancreas, breast, prostate, colon, and lung can- enhances therapeutic efficacy with fewer side effects.
cer, with high affinity to Tf [68–71]. This has prompted
scientists to use the TfR as an active targeting site in Estrogen receptor‑mediated active targeting
the design of novel anti-cancer delivery platforms. TfR Estrogen is a steroid hormone that plays a critical part in
can be employed either for Tf-mediated targeting and maintaining reproductive system function, bone homeo-
internalization of therapeutic agents or to block normal stasis, brain development, and cardiovascular remodeling
receptor function, resulting in cell death [72–74]. In an [84]. Among the three forms (estrone (E1), estradiol (E2),
interesting recent article, Zhang et al. developed a novel and estriol (E3)), E2 is the crucial for the progression of
transferrin protein corona (Tpc)-modified CuGd nano- breast, endometrial, and ovarian cancers [85, 86]. Estro-
platform (Tpc-CuGd) for tumor-targeting photothermal gen function relies primarily on its binding and subse-
and chemodynamic synergistic therapy [75]. quent activation of two structurally different estrogen
In summary, various Tf-modified nanoparticles have receptors (ERα and ERβ) [87]. Therefore, these related
been developed for the targeted delivery of therapeutic receptors are considered members of the nuclear recep-
agents to tumor sites, which can preferentially deliver tor superfamily.
therapeutics into TfR-overexpressing tumor cells by It has been reported that following intracellular uptake
receptor-mediated internalization [76], showing excellent of estrogen-modified nanoparticles by receptor-mediated
antitumor effects with few side effects. endocytosis, intracellular ERs can carry these nanopar-
ticles toward the nucleus for nuclear targeting [88]. Fur-
Human epidermal growth factor receptor 2 thermore, these receptors have been found overexpressed
(HER2)‑mediated active targeting on several tumor cell surfaces. In a recent application,
The HER family, comprising HER1, HER2, HER3, and Kapara and co-workers [89] reported a straightforward
HER4, plays a crucial part in the pathogenesis of vari- and non-destructive 3D surface-enhanced Raman spec-
ous tumors including gastric and breast cancer [77, 78]. troscopy (SERS) imaging strategy to track the cellular
HER-targeting-based strategies may address tumor internalization of AuNPs modified with an anti-ERα Ab
chemoresistance as their associated receptors usually in MCF-7 cells. It was found that these modified nano-
possess tyrosine kinase catalytic activity [79]. Among particles were effectively internalized by tumor cells
these, the HER2 receptor is commonly studied in breast using the ERα receptor-mediated endocytosis process for
cancer as it is overexpressed > 20% of patients [80]. While enhanced tumor treatment.
the HER2 receptor does not have a natural ligand, it can
dimerize with other ErbB family receptors, which results Cluster of differentiation (CD) receptor‑mediated active
in activation of the HER signaling pathways [79]. A sig- targeting
nificant challenge in developing targeted drugs has been The CD receptor family comprises surface receptors
the identification and preparation of HER2-specific mainly present on cancer stem cells (CSCs), including
artificial ligands with specificity and colloidal stability. CD14, CD22, CD36, CD44, and CD133, which can be
Recently, a variety of monoclonal antibodies (Abs) and used as promising delivery targets against tumor metas-
their fragments, as well as some peptide drugs, have been tasis. Among them, CD44, a transmembrane adhesion
glycoprotein, has been commonly used to target recep- chemokine signaling can modulate the normal immune
tors for targeted tumor treatment [90–92]. Hyaluronic function in epithelial cells because CXCR4 plays a signifi-
acid (HA), a ligand with good biocompatibility, has been cant role in normal cell growth and angiogenesis [105].
widely used in CD44 receptor-mediated active target- There is there an urgent need to design novel chemokine
ing delivery systems. It can be readily obtained due to inhibitors that do not disturb the function of healthy cells.
its abundance as a natural polymer compared with poly- A number of LHRH receptors have been found in breast,
mers that require multiple step chemical synthesis [93, ovarian and prostate cancer, but their expression is low
94]. HA-functionalized nanoplatforms can effectively or absent in the corresponding healthy tissues [106, 107].
deliver therapeutic agents to tumor cells through CD44 Therefore, several nanoplatforms modified with LHRH
receptor-mediated active targeting, with an excellent peptides have been explored for the targeted delivery of
cytotoxic profile and tumor kill. For example, Kim et al. therapeutic agents [108–111]. For instance, LHRH pep-
[94] reported a HA modified, trio-stimuli receptive and tide conjugated nanoparticles prepared by Tang and co-
on-demand triggerable nanoplatform for multimodal workers enhanced cellular uptake and tumor suppression
cancer treatment. These HA-enveloped nanoparticles in comparison to the non-LHRH targeted formulations
effectively suppressed tumor growth in comparison to [112]. Moreover, Taheri and co-workers designed LHRH
groups without HA modification. In general, HA is modi- peptide-functionalized methotrexate-encapsulated nano-
fied on the surface of nanoparticles to specifically bind particles with higher therapeutic efficacy against cancer
to CD44 receptors that are overexpressed in tumor cells, [113]. In addition, Zhang’s group reported the anti-cancer
thus mediating tumor endocytosis. In addition, HA has ability of LHRH receptor-targeted mitoxantrone-encapsu-
the tendency to be degraded to smaller fragments in lated versatile nanoplatforms in vivo, demonstrating aug-
the presence of hyaluronidase which is also abundantly mented tumor suppression with the targeted liposomes in
present in the TME [95]. The versatile characteristics of comparison to non-targeted formulations [111]. Although
HA as a targeted and enzyme-responsive ligand make these receptor-mediated strategies have shown potential
it a promising candidate for application in specific drug advantages for drug delivery, several factors, such as ligand
delivery systems. stability, orientation, and density, must be taken into con-
sideration to preserve the function of the targeting ligand.
Other receptor‑mediated active targeting systems
In addition to the receptors mentioned above, other recep- Stimuli‑responsive targeting strategies
tors have also been used to design targeted anti-cancer Unique features of the TME include an acidic envi-
nanoplatforms, including chemokine, biotin, and lutein- ronment, a high concentration of GSH and ROS, and
izing hormone-releasing hormone (LHRH) receptors [96– increased expression of specific enzymes (MMP-2/cath-
100]. For example, chemokine receptor type 4 (CXCR4) epsin B). Therefore, nanoparticles incorporating TME-
is a class of G-protein-coupled receptor that plays an responsive components can pave the way for targeted
important part in tumor metastasis by gathering tumor drug delivery and tumor treatment. In response to these
cells along chemokine gradients. Several peptide-func- endogenous stimuli, alterations in molecular function
tionalized nanoplatforms have been prepared for targeting and dispersion behavior, morphology, and degradation
CXCR4 receptor-positive cancers. For example, Alberi- kinetics can be induced. This facilitates either intracel-
cio et al. developed circular peptide T22-functionalized lular internalization or escape from endosome/lysoso-
mesoporous silica for the effective delivery of chemothera- mal degradation and release of pharmaceutical active
peutic agents to tumor cells [101]. Wang and co-workers ingredients [114]. In addition to endogenous respon-
prepared epirubicin-encapsulated polymeric nanoparticles sive nanosystems, some exogenous stimuli-responsive
that clearly improved therapeutic efficacy in hepatocellular nanoparticles also show beneficial targeting behavior by
carcinoma by conjugating the LFC131 peptide to increase utilizing controllable external factors, such as lasers, tem-
the affinity [102]. Similarly, Murakami’s group also devel- perature, ultrasound, and magnetism. Several examples
oped cellulose nanoparticles with the LFC131 peptide of endogenous and exogenous responsive nanoplatforms
for targeted tumor treatment [103]. Xiao et al. designed a are presented below (Fig. 4).
novel nanoplatform to target CXCR-4 to effectively induce
p53 expression in hepatocellular carcinoma models. Com- Endogenous Stimuli‑responsive targeting strategies
bining the CXCR4-targeted p53 mRNA nanoplatform with Redox‑responsive targeting strategies
anti-PD-1 treatment effectively induced cellular repro- Redox species in tumor cells form a complex antioxidant
gramming and immune components of the tumor micro- defense system to modulate redox homeostasis, play-
environment in established hepatocellular carcinoma ing an important role in the cell life cycle [115]. Com-
models [104]. It should be noted that the suppression of mon reactive oxygen species (ROS) include hydroxyl
radicals (·OH), singlet oxygen (1O2), and hydrogen perox- ROS‑responsive targeting strategies Hypoxia, which can
ide (H2O2). It should be noted that H2O2 is a stable and cause tumorigenesis and cancer progression, has been
nontoxic ROS, while others have a short half-life and can considered as a significant biomarker in cancer theranos-
be effectively transformed into powerful toxic reagents tics and targeted treatment. Moreover, it is controlled by
[116, 117]. On the one hand, H2O2 can be used as a sub- the overgeneration of VEGF and hypoxia induced factor
strate for O2 production with the aid of a specific enzyme (HIF-1α) in tumor cells [130], resulting in decreased sen-
to alleviate tumor microenvironment hypoxia in some sitivity of cancers to radiotherapy (RT), causing chemore-
O2-demanding therapeutic strategies [118]. On the other sistance and also greatly affecting the efficacy of O2-related
hand, the H 2O2 can also be converted into other highly treatments, such as photodynamic therapy (PDT) and
active ROS, including 1O2, O2·− and ·OH [116]. This sonodynamic therapy (SDT) [131]. Recently, researchers
increased ROS can result in oxidative stress, such as lipid have developed versatile ROS-responsive nanoparticles
peroxidation (LPO), and protein and DNA impairment through catalase (CAT)-mediated tumor site-specific
[119]. In addition, glutathione (GSH), as an antioxidant, O2 generation to alleviate hypoxia for enhancing tumor
is commonly distributed in tumor cells at concentrations treatment [132]. For instance, Zhang et al. developed
up to 2–10 mM, playing a significant role in consuming liposomes loaded with a cisplatin-prodrug functional-
ROS and modulating redox homeostasis [120, 121]. Fur- ized phospholipid and CAT [133], alleviating the chem-
thermore, a high GSH concentration can make tumor oresistance caused by hypoxia. Further, the liposome
cells resistant to various treatments [122]. Therefore, it encapsulation also endowed the prepared nanoplatforms
is advantageous to develop redox-sensitive nanoparti- with satisfactory biocompatibility and a high tumor accu-
cles for the delivery of therapeutic agents to trigger treat- mulation profile. Treatment with the designed liposomes
ments such as chemodynamic therapy (CDT) (Fig. 5). In induced the highest level of DNA impairment in tumor
addition, to further improve the therapeutic profile, ROS cells exposed to X-rays in comparison to the control
generation combined with GSH depletion can effectively group. In addition, a range of nanocarriers with CAT
disturb redox homeostasis to augment oxidative stress, mimicking activity, including MOF, M nO2, CeO2, Pt, and
thus resulting in tumor cell apoptosis [123]. ROS are gen- Pd [131, 134–138], have also shown greatly potential in
erated by the partial reduction of O2 which is necessary nanomedical applications. It should be noted that MnO2
for maintaining the normal function of aerobic organisms is well known to convert H 2O2 into O2 under the action of
using energy provided from four electron reduction reac- the acidic TME with the disruption of M nO2-based nano-
tion [124–129]. As shown in Table 2, most efforts have particles [138, 139]. These ROS-responsive nanoparticles
been to develop ROS-responsive building blocks, which capable of stimulating tumor site-specific O 2 production
can be combined with chemotherapeutics to achieve provide a practical strategy for improving the sensitivity
excellent antitumor activity with few side effects. of RT and chemotherapy.
Fig. 4 Schematic representation of exogenous and endogenous stimuli-responsive nanoplatforms for tumor therapy
Fig. 5 (A) Schematic illustration of amplified oxidative stress based on intracellular ROS for incurring tumor cell apoptosis. B Schematic illustration
of the anti-metastasis performance of the GSH-responsive nanoplatforms
Hydroxyl radicals (·OH) are not only an important been devoted to replenishing H2O2 in tumor cells [143].
component of ROS, but also the main product of the Fen- Among these strategies, iron-based nanoparticles have
ton reaction for tumor-targeted therapy [140]. Moreover, been widely applied to generate highly toxic ·OH for
tion (50 – 100 Μm) is not sufficient to generate adequate

the unique characteristics of slight acidity and overpro- tumor treatment. As the intratumoral H 2O2 concentra-
duction of H 2O2 in the TME offer a suitable environ-
ment and reactants for the Fenton reaction compared to amounts of ·OH, Gao et al. prepared Au-Fe3O4-based
normal cells. Tang et al. reported on the use of chemo- nanoparticles for nanocatalytic cancer treatment. In this
dynamic therapy (CDT using Fenton or Fenton-like reac- nanosystem, Au first catalyzes intracellular glucose oxi-
tions for ·OH-producing tumor treatment [141]. Another dation into gluconic acid and H2O2. The F e3O4-triggered
promising application of endogenous H2O2 in the TME Fenton reaction then converts H2O2 into ·OH radicals
is to activate CDT for specific cancer treatment [142]. inducing tumor cell death [144]. Both in vitro and in vivo
To achieve this, a number of H 2O2-sensitive nanopar- results confirmed that the designed nanoparticles pre-
ticles have been developed, and many efforts have also sented a satisfactory tumor inhibition ratio. Many other
Table 2 ROS-responsive building blocks for cancer treatment

Type of chemical bond Nanoplatform Tumor model Therapy strategies Refs.
Thioketal linker Polyprodrug NPDOX/Cy Breast cancer Chemotherapy [493]

Phenylboronate ester G5.NHAc-Toy@TF nanocomplexes Breast cancer Chemotherapy, CDT [494]
pPBA(TL)-MN Breast cancer Immunotherapy [495]
Bilirubin Dox@bt-BRNPs Cervical carcinoma Chemotherapy [496]
TH-302@BR-Chitosan NPs Cervical carcinoma Chemotherapy PTT [497]
Gallic acid-ferrous nanocomplex BSO/GA–Fe(II)@ liposome Breast cancer CDT [119]
Ru nanoparticle HA-Ru NAs Breast cancer PTT, PDT, CDT [498]
FePt nanoparticle FePt/MoS2-FA nanocomposites Breast cancer Immunotherapy, PTT [499]
Manganese ferrite nanoparticle (MFN) MFMSN-Ce6 Melanoma SDT [500]
Horseradish peroxidase Lipo@HRP&ABTS Breast cancer PTT [501]
PEG-TiO1+x NRs Breast cancer SDT, CDT [502]
Catalase CAT@Pt (IV)-liposome Breast cancer Chemotherapy, RT [133]
CAT@HA-HMME NPs Colorectal cancer SDT [503]
Bis(3,4,6-trichloro-2-(pentyloxycarbonyl) POCL Cervical carcinoma PDT [504]
phenyl) oxalate
iron-free Fenton nanocatalysts including transition promotes H2O2-sensitive transformation from insoluble
metal-based, precious-metal-based, sulfide-based nano- to soluble forms. Poly (propylene sulfide) conjugated with
catalysts and their composites multifunctional radical PEG can rapidly self-assemble into nanoparticles and
therapeutics have been developed [145]. decompose upon confrontation with H 2O2, suggesting
Recently, Chen and colleagues prepared copper per- great promise as a delivery platform. Overall, nanopar-
oxide (Cu2O2) nanoparticles with the features of revers- ticles containing H2O2-sensitive groups are expected to
ible degradation to generate self-supplying H2O2 through become more widely used in stimuli-triggered disintegra-
changes in Ph [146]. The H2O2 could be effectively cata- tion and specific cancer treatment [150, 151].
lyzed by C u2+ to generate highly toxic ·OH. These nano-
particles showed improved tumor inhibition efficacy in Reactive nitrogen species (RNS)‑responsive targeting strat‑
comparison to the controls. Additionally, H2O2 has also egies NO, the first gas molecule for therapy, has attracted
been used for NO-based gas treatment. This has been attention because of its excellent diffusivity and cell mem-
called a “green” treatment approach for cancer therapy, as brane penetration, endowing it with broad biological
it shows minimal toxicity for normal tissues while offer- activities and therapeutic potential [152–158]. It has been
ing metabolic benefits that are not achievable through reported that matrix metalloproteinases (MMPs), which
chemotherapy or other traditional therapeutic modali- comprise a family of enzymes that can degrade matrix
ties [147]. For example, Chen and colleagues developed proteins, are capable of depletion of collagen through acti-
mesoporous silica nanoparticles as biocompatible nano- vation of NO, resulting in improved penetration ability of
vehicles for the delivery of arginine and glucose oxidase the prepared nanoparticles [159, 160]. In addition, NO
(Gox) [148]. These nanoparticles used encapsulated Gox can react with 1O2 to generate highly toxic peroxynitrite
to provide a degrading glucose reaction to increase intra- (ONOO−) which has a stronger tumor cell killing abil-
cellular H2O2 concentration, which can then oxidize argi- ity [161]. ONOO- can convert pro-MMPs into MMPs to
nine into NO under the action of specific NO synthase. degrade the extracellular matrix to enhance the penetra-
As the levels of glucose increase, the tumor microenvi- tion ability of nanoparticles and induce DNA impairment.
ronment became more acidic, allowing H 2O2 to facilitate NO and ONOO- can cause mitochondrial dysfunction by
the NO production. After treatment with the designed reducing mitochondrial membrane potential and inhib-
nanoparticles, tumor volumes were considerably reduced iting the generation of ATP, which effectively suppresses
and the mice had longer survival times. In another mode, ATP-related tumor-derived vesicles and tumor metas-
H2O2 can be used as a stimulus for the disruption of nan- tasis [162]. Moreover, the derived RNS and superoxide
oparticles, leading to controllable release. For instance, can effectively kill cancer cells by inducing nitrosative or
a novel oxidation-sensitive polymeric carrier has been oxidative stress, DNA or mitochondrial impairment and
used to prepare antitumors nanoplatforms [149]. Among improving inflammatory reactions, resulting in acceler-
them, poly (propylene sulfide) as a hydrophobic block ated cell apoptosis [147, 163–165]. However, there are still
some concerns regarding the delivery of NO by different novel nanoprodrug had a high CPT loading efficiency
nanomaterials due to difficulties in obtaining efficient and exhibited rapid drug release when exposed to GSH.
encapsulation and precise release [166]. To overcome the Additionally, the photothermal effect of the cocaine dyes
drawbacks of the current NO delivery carriers and NO further facilitated disulfide linker cleavage. The encap-
donors, an interesting approach was reported to transport sulated croconaine dyes endowed this nanoparticle with
NO for tumor treatment using prodrug self-assembling NIR fluorescence and photoacoustic imaging properties
nanoplatforms of NO donors. Briefly, phenylsulfonyl- for tumor treatment.
furoxan was used as the NO donor in the synthesis of a Platinum drugs (e.g., cisplatin, carboplatin and oxali-
prodrug using ester and disulfide bonds. The insertion of platin) currently remain the most commonly used
disulfide bonds facilitates the self-assembly of polymers chemotherapeutic agents against a number of tumors
in solution. Subsequently, the multiresponsive tumor- [190, 191]. However, there are numerous problems with
targeting NO nanoparticles can be obtained by adding FA these drugs in clinical use, such as lack of specificity and
onto the surface, which can achieve the effective delivery severe side effects on normal organs. Therefore is a grow-
of NO to tumor regions, leading to accurate NO release ing tendency to develop prodrug-based nontoxic Pt(IV)
and inducing tumor cell apoptosis [167]. Researchers have s that can be converted into highly toxic Pt(II) through
also developed other NO donors, such as Roussin’s black the reduction of GSH [192]. Farokhzad’s group developed
salt, metal NO complexes, and S-nitrosothiols [168–171]. self-assembled nanoparticles comprised of PEGlipid and
NO may also relieve hypoxia in the tumor area through Pt (IV) prodrug for tumor treatment [193]. On one hand,
vasodilation, which promotes PDT efficacy [172], further this nanoscale strategy facilitated the delivery of cargoes
improving the combined effects of PDT and NO in can- across cell membranes into cells by endocytosis. On
cer therapy. To improve penetration into tumor tissue in another other, these prodrugs had a GSH-depleting fea-
PDT-mediated tumor treatment, researchers typically ture, resulting in the release of Pt(II) to act on DNA and
combine rare-earth up-conversion nanomaterials with trigger tumor cell apoptosis.
different photosensitive therapeutic agents [173, 174]. In addition to the above GSH-responsive nanoparti-
However, this poses new risks in the preparation and cles, multivalent metal ions such as Fe2+ and Fe3+ Cu+
biosecurity of such nanoparticles. The combination of and Cu2+ and Mn2+ and Mn4+also show GSH-responsive
ROS and RNS responsive strategies into the same nano- behavior due to a shift in valency, [194]. These reduced
particles with good biological safety can be expected to metal ions can be further applied for diagnosis or
provide an efficient and all-in-one anticancer treatment. improved treatment. In one example, ultrasmall (4 nm)
cerium oxide nanoparticles (CeO2 NPs) were rapidly
GSH‑responsive targeting strategies A number of nano- etched, leading to the opening of nanochannels in the
carriers comprised of disulfide bonds, carbon-diselenide mesoporous silicon nanoparticles when exposed to vita-
bonds, diselenide bonds, or a sulfonyl group [175–182] min C or GSH, resulting in controlled antitumor drug
have been prepared by cross-linking reactions. Overgen- release [195]. Recently, our group prepared versatile Cu-
erated GSH can effectively break various disulfide bonds, MOF nanoparticles loaded with VK3 for enhanced CDT
thus causing disintegration of nanoparticles and accurate by regulating GSH and H 2O2 in the tumor microenviron-
cargo release in cancer cells. It should be noted that nano- ment [196, 197]. Cu+ and Cu2+ showed better catalytic
platforms with disulfide bonds embedded in mesoporous capability than classical Fe-dependent Fenton agents.
silica nanoparticles show fast biodegradation and are The satisfactory antitumor effects presented by these Cu-
emerging as promising nanovehicles [183]. based nanoparticles, and the cascade-enhanced chemo-
For the development of GSH-sensitive nanoplatforms, chemodynamic therapy approach provide an opportunity
the co-assembly of amphipathic block copolymers and for the application of such novel nanoplatforms for HCC
therapeutic agents with GSH-responsive groups into sev- treatment. Furthermore, future advancements, such
eral nanosystems (such as liposomes, nanoparticles, and as improved targeting, can effectively improve the effi-
micelles) has been considered as a potential application cacy and use of such approaches, which should be ben-
approach [184]. Nanoplatforms bearing GSH-cleavable eficial to cancer treatment [196, 197]. Additionally, the
prodrugs have also been developed, which can be effec- consumption of GSH plays an important role in metal-
tively modulated to toxic therapeutic agents by exces- based chemodynamic therapy. For instance, Liu et al.
sive intracellular GSH [185–188]. For example, Sun et al. developed advanced metal-based nanoparticles through
loaded a trimeric prodrug into FA functionalized polylac- chemodynamics for multimodal tumor treatment [198].
tic-coglycolic acid hybrid nanoparticles, where the chem- GSH acted on the designed nanoparticles and effectively
otherapeutic camptothecin (CPT) was conjugated to reduced Mn4+, Mn3+, and Cu2+ into Mn2+ and Cu+,
NIR croconaine dyes through disulfide bonds [189]. This accompanied by GSH consumption. Inductively coupled
plasma optical emission spectrometry (ICP-OES) was tumor accumulation of the loaded therapeutic agents and
used to support the rapid release of Cu and Mn from the facilitating the release of cargoes in the acidic tumoral
nanoparticles in an acidic environment containing GSH. microenvironment [205]. Currently, researchers typically
The nanoparticles displayed specific recognition and use changes in chemical structure (such as changes in
homotypic targeting profiles to MCF-7 cells. Combin- hydrophilicity through deprotonation and protonation)
ing metal ions with GSH-consumption in the TME could and acid-sensitive chemical bonds to design pH-respon-
become a more promising targeted strategy for CDT sive nanoplatforms (Fig. 6). Additionally, the designed
pH-sensitive formulations usually have the ability to pro-
ROS and GSH dual‑responsive tumor‑targeting strat‑ tect several therapeutic agents and vehicles for tumor
egy As mentioned above, intracellular redox regulation therapy from being trapped in endosomes [206, 207].
has been considered an effective strategy against cancer. Generally, the encapsulation of chemotherapeutics inside
However, the ROS produced from the catalytic oxida- pH-responsive nanoparticles is an efficient approach for
tion of H
2O2 can be removed by the overgenerated GSH, prolonging the blood circulation time of the encapsu-
compromising therapeutic interventions. To overcome lated agents and their retention inside the nanoparticles
this, selective enhancement of oxidative stress through in a physiological environment. Moreover, pH-responsive
depleting GSH levels and simultaneously elevating ROS nanoparticles are also able to improve the pharmacoki-
concentrations can be a specific and promising strategy in netics and biodistribution of the encapsulated payload.
cancer treatment [199]. For instance, Liang and colleagues This is essential for delaying metabolism and the subse-
designed an oxidative stress-amplified nanoplatform for quent release of drugs.
disturbing mitochondrial redox balance, which com-
prised atomically dispersed Au anchored onto a carbon- Protonation and deprotonation‑based nanoplat‑
dot surface modified with cinnamaldehyde and triph- forms Protonation and deprotonation are widely used
enylphosphine [200]. The acidity of endosomes facilitates mechanisms for pH-sensitive nanocarriers in tumor
the dissociation of cinnamaldehyde. Subsequently, the treatment. pH-responsive nanoplatforms including
nanoparticles rapidly react with GSH, accompanied by polyelectrolytes, such as poly(aspartic acid-graft-imi-
ROS generation, resulting in the elevation of ROS and the dazole), cationic poly(β-amino ester) (PBAE), anionic
simultaneous reduction of GSH. As a result, levels of mito- poly(Asp), PDMAEMA, polysulfonamide, poly(histidine)
chondrial GSH in tumor cells were obviously decreased (poly(His)), and poly(acrylic acid) (PAA), are shown in
after incubation with the prepared nanoparticles. In addi- Table 3. In an advanced strategy to design biocompatible
tion, the prepared nanoparticles with enhanced oxida- nanoparticles, it has also been proposed that biodegrad-
tive stress possessed excellent anticancer effects against able materials such as enzyme-responsive chitosan and
HepG-2 tumors. These groups of designed nanoparticles certain polypeptides can be used for protonation and
also showed prolonged survival times and few side effects deprotonation-based nanomaterials through function-
against various tumor models, which can be attributed to alization with an acid-responsive group to the backbone
the fact that normal tissues, unlike the TME, do not have of biodegradable materials [208–210]. These materials
high redox levels. generally contain –COOH as anionic groups and –NH2
as cationic groups combined with other hydrophobic
pH‑responsive targeting strategies or hydrophilic molecules, which can be further used in
pH-sensitive nanocarriers have been extensively explored pH-responsive nanoplatforms through protonation and
to design versatile nanoplatforms for targeted drug deliv- deprotonation.
ery. The TME usually has a lower extracellular pH (pHex) Cationic materials with -NH2 groups can effectively
with a mean value of ~ 6.5 in comparison to healthy tis- protonate in an acidic environment and show excellent
sue [201]. Generally, compared with healthy cells, tumor hydrophilicity, while they can deprotonate in a neu-
cells rapidly consume glucose for glycolysis with rapid tral environment to show hydrophobicity. In contrast,
lactate production to obtain the energy required for anionic materials with –COOH groups [211–214] can
maintaining their proliferation regardless of oxygen also deprotonate and protonate in the opposite way.
content; consequently, the higher metabolism rate of For instance, the groups of imidazole can be easily pro-
tumor cells has been recognized as a major cause of the tonated under acidic conditions, as they have a pair of
acidic TME [202]. Additionally, tumor cell, lysosomes electrons on the unsaturated N atoms, leading to the con-
and endosomes also have a lower pH (endosomal pH version of hydrophobic to hydrophilic states, which can
(pHen)) in comparison to pHex [203, 204]. Therefore, incur disintegration of the nanocarriers and consequently
pH-responsive nanoplatforms have been developed as release the loaded therapeutic agents. Besides, poly(His)-
an effective tumor treatment tool, greatly enhancing the PEG shows obvious nanoscale core–shell micelles in a
Fig. 6 Schematic illustration of pH-responsive nanoplatforms for the delivery of therapeutic agents. The nanoplatforms can effectively accumulate
in the tumor sites via the EPR effect. In the tumor microenvironment, acidic conditions can effectively trigger drug release for tumor treatment
neutral environment consisting of the hydrophilic PEG released in an acidic environment because of the destruc-
shell and hydrophobic cores of poly(His) by deprotonation of the hydrophobic cores. In another example, Oh
tion. However, the protonation of poly(His) responds et al. also prepared pH-responsive micelles using amphi-
to His groups and destabilizes micelles because of the philic polyelectrolytes for docetaxel delivery. Similarly,
reduced hydrophobicity of poly(His) at pHex. Further, the prepared micelles exhibited good colloidal stabil-
the poorly soluble therapeutic agents encapsulated in ity under physiological conditions, while they became
the core of the pH-responsive micelles can be effectively unstable due to protonation of the imidazole group under
Table 3 pH-responsive building blocks for tumor treatment

pH-sensitive building block Therapeutic agent Tumor model Therapeutic application Refs.
Poly(2-(hexamethyleneimino)ethyl methacrylate siBRD4-loaded TCPA2-NPs Prostatic cancer LNCaP-bearing mouse GT [477]

HRNMs Glioblastoma Chemotherapy [478]
Poly(diisopropanol amino ethyl methacrylate) GPDPA NPs Glioblastoma Chemotherapy PTT [479]
Benzoic-imine bond CA-MTX NPs Cervical carcinoma Chemotherapy [480]
nBSA-Dox Hepatocellular carcinoma Chemotherapy [481]
NdIIIIP-N = CH-PEG Cervical carcinoma Chemotherapy PTT [482]
DOX-ICM Glioblastoma Chemotherapy [483]
Au@PP/RA/siRNA Pancreatic cancer Chemotherapy [484]
Pyridine-2-imine Gold nanomachine Breast cancer PTT [485]
PMNP-DOX@RBC Breast cancer Chemotherapy, CDT [486]
Amide bond DOX-CC-NP Squamous cell carcinoma Chemotherapy [19]
PDNBF NPs Breast cancer Chemotherapy PTT [487]
Nanodrug complex MONCs Breast cancer Chemotherapy PDT [488]
B780/Qu NPs Breast cancer Chemotherapy PDT, PTT [98]
Gadolinium oxide Gd2O3 NSs Melanoma Chemotherapy [489]
FS-GdNDs Breast cancer PTT [490]
Triplex DNA sequence NLNs/DOX Breast cancer Chemotherapy [491]
DNA Conjugated AuNPs Breast cancer Chemotherapy PTT [492]
acidic conditions. Therefore, the docetaxel-encapsulated ticular, acid-sensitive chemical bonds have been inten-
micelles have pH-responsive release behavior due to sively investigated for pH-responsive nanocarriers, such as
structural changes induced by protonation of the imi- esters, imines, and hydrazine. These acid-sensitive bond-
dazole groups in the amphiphilic polyelectrolytes. pH- based nanoplatforms have been proven to be relatively
responsive release can also lead to high stability in blood stable in physiological environments but are easily bro-
circulation, a decrease in the toxicity of healthy tissues, ken via nucleophilic substitution reactions under acidic
and increased drug availability. conditions [216]. Further, the acid-sensitive bonds can
Additionally, some materials with anionic polyelectro- be directly conjugated to the therapeutic agents as labile
lytes have also been used to prepare pH-sensitive nano- groups in nanoparticles. For example, with the protona-
carriers for drug delivery [215]. However, the strategy tion of labile compounds containing C=N bonds (such as
of taking advantage of anionic amphiphilic molecules hydrazone bonds, imine groups, and oxime bonds) under
to prepare pH-responsive and tumor-targeted nanocar- acidic conditions, they can be readily susceptible to nucle-
riers can be different from that utilizing cationic mate- ophilic substitution by H 2O because of the increased elec-
rials. Under acidic conditions, such as pHen and pHex, trophilicity of carbon atoms [217–220]. Hydrazone link-
anionic polymers containing -COOH groups can exist as ages in particular, with satisfactory acid responsiveness
protonated (hydrophobic) units and are not applicable and a fast degradation rate, have been widely used in dif-
to tumor-targeted micelles from amphiphilic polymer ferent pH-responsive nanoplatforms such as liposomes,
blocks rich in anionic groups. As a result, anionic poly- nanoparticles, and micelles [210, 221–225]. Additionally,
mers can be encapsulated with some chemotherapeutics acid-responsive groups can also be applied to improve
such as DOX using hydrophobic interactions in physi- the limited cargo release from the nanoparticle core and
ological environments, and therapeutic agents can be target-cell interactions because of PEGylation. For exam-
effectively released for specific tumor treatment under ple, Wu et al. synthesized hydrazone linker-functionalized
acidic conditions via weakened interactions owing to liposomes to address the problems with PEGylation. As
protonation. expected, the hydrazone bond-functionalized liposomes
exhibited satisfactory lysosomal escape properties and
Acid‑sensitive bond cleavage‑based nanoparticles As enhanced tumor accumulation in comparison to normal
previously described, the acidity differences between the liposomes [226]. However, imine bonds have poor stabil-
various compartments of tumor cells and between tumors ity under physiological environments due to the loss of
or healthy tissues have received widespread consideration mesomeric effects in comparison to hydrazone bonds
for designing pH-responsive chemical structures. In par- [227]. Therefore, researchers have made significant efforts
to improve the stability of imine bonds by introducing tion showed clearly enhanced DOX release under simu-
strong π–π conjugated systems such as benzene rings lated tumor microenvironment conditions and in tumor
[228, 229]. For example, Wang et al. prepared versatile cell models [235]. In addition, Zhang’s group synthesized
biomimetic nanoparticles based on formyl benzoic acid- camptothecin-encapsulated mesoporous silica nanopar-
PEG-maleimide functionalized mesoporous silica against ticles surface functionalized with targeting cRGD and
metastatic triple-negative breast cancer. After loading of MMP-2 responsive fluorescence imaging groups, acting as
immune adjuvant and photothermal therapeutic agents, a diagnostic platform as well as for tumor location. These
the immune peptide was then linked to the surface of advanced nanoplatforms were able to efficiently undergo
nanoparticles through acid-responsive benzoic-imine enzymatic hydrolysis in overexpressed MMP-2 environ-
bonds. It was applied to the therapy of metastatic triple- ments to improve tumor treatment by the release of their
negative breast cancer through immune remodeling and cargoes [236]. Further, some amphiphilic block copoly-
photothermal ablation [230]. Taken together, these low- mers (such as PCL-PEG) are suitable for the preparation
pH-responsive nanoparticles can effectively release the of versatile delivery platforms against cancer. For instance,
encapsulated chemotherapeutic agents upon encounter- PTX-encapsulated PEG-PCL nanoparticles function-
ing the acidic TME in targeted cancer therapy. alized with activated low molecular weight protamine
showed satisfactory targeted glioma effects. Further, these
Enzyme‑responsive targeting strategies advanced nanoparticles also exhibited enhanced MMP-
Enzymes, being a significant component of the nano- dependent cellular internalization, increased cytotoxic-
biotechnology toolbox, have exceptional biorecognition ity, and augmented tumor suppression in glioma models
abilities as well as excellent catalytic properties. Gener- [237]. In another study, Yang et al. prepared a versatile
ally, abnormal enzyme expression observed in cancer nanoparticle based on MMP-sensitive Au nanoparticles
provides many opportunities for designing targeted nan- for tumor-specific photoacoustic imaging-guided tumor
oparticles modified with enzyme-responsive linkages. treatment and drug delivery. The Au nanoparticles could
Recently, many smart nanoparticles have been prepared be further grafted with complementary DNA strands,
for intracellular as well as extracellular tumor-specific functionalized with PEG and conjugated with therapeutic
drug delivery based upon enzyme expression at the target agents through MMP-responsive peptides and thermal-
site. sensitive linkers, respectively. As a result, the developed
nanoparticles showed augmented efficiency in tumor
MMP‑responsive nanoplatforms Matrix metallopro- treatment and photoacoustic imaging in comparison to
teinases (MMPs), which are overexpressed in various MMP-inert nanoparticles [238]. Similarly, hydrophilic
types of tumors, are closely related to cancer patho- siRNA and poorly soluble drugs could be effectively code-
physiology. MMP-2 and MMP-9 in particular have been livered using versatile micelles prepared by MMP-2-re-
explored for preparing enzyme-responsive nanoplatforms sponsive copolymers. The prepared nanoplatform showed
[231, 232]. For example, Yamada et al. prepared two PTX satisfactory colloidal stability and enhanced endocytosis
prodrugs by conjugating an octapeptide (AcGPLGIAGQ) efficiency in different tumor cell lines and significant pas-
with PTX at different sites that could be effectively broken sive targeting behavior in tumor-bearing models. Mallik
down by MMP2 in the tumor microenvironment. These et al. prepared an MMP-9 responsive nanoplatform using
nanoparticles can effectively release PTX to inhibit can- collagen-simulated lipoprotein conjugated to PEG cleav-
cer cell proliferation [233]. Among various natural materi- able polymers to encapsulate Gem. The designed enzyme
als, gelatin is an example of a biocompatible polymer that stimuli-responsive nanoparticles demonstrated a faster
can be degraded by MMPs and promote cargo release in Gem release rate treated with MMP-9 and a higher tumor
tumor sites. For instance, Wang et al. developed MMP- inhibition ratio in comparison to MMP-inert nanoparti-
responsive PVA-peptide conjugates for achieving self- cles [239]. Yang’s group [240] designed an advanced MMP
assembly with enhanced tumor accumulation, capable stimuli-responsive nanoplatform encapsulated with the
of improving PD-L1 blocking efficiency for augmented chemotherapeutic agent curcumin using a block copoly-
immunotherapy. Once the self-assembled nanoplatforms mer with surface-adsorbed peptides that could improve
entered the TME, the enzyme-cleavable peptide could be endocytosis. The prepared nanoplatform showed a sus-
immediately degraded under the action of overexpressed tained curcumin release behavior under physiological
MMPs to effectively release cargoes for cancer treatment conditions, while release could be accelerated under con-
[234]. Furthermore, gelatin-functionalized DOX-loaded ditions that mimic the tumor microenvironment. There is
mesoporous silica nanoparticles have been applied for the no doubt that these designed MMP-responsive nanopar-
delivery of therapeutic agents against MMP-9 overgener- ticles present excellent tumor specificity and therapeutic
ated in cancer. As expected, the prepared nanoformula- efficacy in cancer models with few side effects
Heparanase‑responsive nanoplatforms Glycosamino- only in tumor cells but also in tumor-related endothelial,
glycans and structural proteins together constitute the fibroblast, myoepithelial, and osteoclast cells as well as
matrix of the tumor tissues, of which the main compo- leukocyte cells [248]. A great number of studies have been
nent of glycosaminoglycans is heparan sulfate proteogly- undertaken on the design and development of cathepsin-
can [241]. Furthermore, heparan sulfate proteoglycan is responsive nanoplatforms, particularly on Gly-Phe-Leu-
actively involved with various biological factors (including Gly, which has been commonly applied as a spacer that
VEGF, TGF-β, and b-FGF) that play an important role in can be effectively degraded in overexpressed cathepsin B
the interaction between normal cells and tumors. In addi- environments [249]. For example, Xia et al. prepared a pH
tion, some reports have pointed out that highly metastatic and cathepsin B dual-responsive nanovaccine that specif-
and malignant cancers frequently over generate hepara- ically targeted endosomal Toll-like receptors (TLRs) for
nase-1, which can degrade HSPGs in the tumor micro- enhanced tumor vaccination. In vivo results showed excel-
environment, causing enhanced secretion of the above lent prophylactic and antitumor effects of the nanovac-
bioactive factors and the consecutive triggering of related cine against tumor-bearing mice. This endosome-targeted
pathways resulting in cancer metastasis, epithelial-mes- responsive nanovaccine approach provides a promising
enchymal transition, and neovascularization. Addition- delivery platform for adjuvants to promote the design
ally, the new spaces formed in the matrix can also result and preparation of cancer nanovaccines [250]. Accurate
in cancer invasion and metastasis [242]. It has also been assessment of cathepsin B expression in vivo may pro-
reported that heparanase-1 can effectively degrade hepa- vide a potential approach for early tumor diagnosis [251].
rin, suggesting a potential novel nanovehicle with hepara- Taking advantage of precise photoacoustic imaging, an
nase sensitivity for drug delivery. intelligent photoacoustic probe Cypate-CBT, which could
An example of utilizing heparin-prepared nanoplat- effectively assemble into cypate-containing nanoprobes in
forms is to bind heparin molecules via GSH-responsive response to overgenerated GSH and cathepsin B in tumor
disulfide bonds to construct heparin-based nanogels cells, was prepared by Liang’s group [251] for the accurate
[243]. Another approach involved the construction of a and specific monitoring of cathepsin B. In comparison
nanocomplex through electrostatic interactions between to unmodified Cypate, this nanoprobe showed a higher
protamine and heparin for effective loading of positively photoacoustic signal in cathepsin B-positive breast can-
charged therapeutic agents. Researchers have devel- cer models, supporting the intracellular accumulation of
oped similar versatile nanoparticles with polyelectrolyte the nanoprobes after cathepsin B-triggered self-assembly.
complexes encapsulating small therapeutic agents [244]. The cathepsin B-responsive nanoprobe can be employed
Isothermal titration calorimetry and real-time dynamic as an efficient photoacoustic imaging agent for the early
swelling spectroscopy have been used to explore the diagnosis and targeted therapy of cancer.
underlying mechanisms and principles for the fabrication
of advanced nanoplatforms via intermolecular electro- Hypoxia‑responsive targeting strategies
static interactions [245]. During optimization of the man- Hypoxia, considered a significant hallmark of solid
ufacturing process, the polyelectrolyte nanocomplex can tumors, has been observed in more than 60% of cancers
be developed with appropriate negative surface charges [252, 253]. The partial pressure of O 2 (pO2) is generally
and particle size [246]. 1,2-Dioleoyl-3-trimethylammo- approximately 40–60 mm Hg in normal tissues while it
nium-propane (DOTAP), a positively charged phospho- is less than 10 mm Hg in tumor tissues, and even as low
lipid compound widely applied to construct cationic as 0–2.5 mm Hg in some cases [254–256]. The O2 con-
liposomes, has been applied to encapsulate hydrophobic sumed by tumor cells exceeds supply leading to this path-
chemotherapeutic agents through liposomes formation ological phenomenon. Abnormally vigorous metabolism
[247]. When codelivered therapeutic agents nanoplat- and cell growth in tumor cells can deplete intracellular
forms enter the tumor microenvironment, overexpressed O2. Secondly, the vascular system in the tumor tissue
heparanase-1 can rapidly recognize the outer heparin is disordered, resulting in an insufficient supply of O 2.
shell and cleave it, resulting in the release of cargoes Finally, the short O2 diffusion distance (less than 200 μm)
for tumor cell kill [242]. This also causes the positively cannot meet the demand of tumor cells further away
charged nanoparticle core to be exposed to the cancer from the blood vessels [257–259]. To better adapt to this
cells, and efficient endocytosis of nanoparticles by tumor harsh living environment, hypoxic cancer cells must alter
cells can be achieved with this approach. some of their biological characteristics, such as upregu-
lating the levels of HIF-1α, carbonic anhydrase IX (CA
Cathepsin‑sensitive nanocarriers Recently, researchers IX), and other enzymes [260].
have demonstrated that a variety of cathepsins are overex- As a result, enhanced cancer metastasis and poor ther-
pressed in different types of tumors. These are found not apeutic effects are usually evident in hypoxic-stimulated
tumors [261, 262]. For instance, the hypoxic microenvi- cells, such as azoreductase, nitroreductase, methio-
ronment can result in overexpression of HIF-1α, which nine synthase reductase, inducible nitric synthase and
is capable of modulating gene expression relevant to DT-diaphorase (DTD) [274, 275]. Hence, considerable
tumor proliferation, invasion and metastasis to facilitate efforts have been made to develop hypoxia-responsive
the resistance to O 2-dependent antitumor strategies, nanoplatforms that can be activated by these enzymes
such as chemotherapy, PDT and RT [263–266]. In addi- for enhanced tumor treatment based on the above find-
tion, hypoxia-adapted tumor cells generally do not have ings [274, 276, 277]. Hypoxia-responsive chemical bonds
the rapid division characteristics of normal tumor cells, (Table 4), including nitro groups, azo groups, quinone
so they are not sensitive to conventional chemotherapeu- and N-oxide compounds, are also applied in the con-
tic agents that interfere with DNA replication [267, 268]. struction of hypoxia-responsive nanoparticles. They can
Further, O2 plays an important part in repairing DNA change their conformation and physicochemical char-
dysfunction after radiation treatment (such as X-ray and acteristics such as hydrophobic features and electron
γ-ray) during RT, and it is the source of PDT or SDT- affinity by gaining or losing their electrons [278, 279]. As
mediated ROS applied to fight tumors [267, 269–273] anticipated, such hypoxia-responsive nanoparticles have
Hypoxia of tumor tissue is generally considered to been found to exhibit satisfactory performance for drug
indicate poor prognosis for tumor treatment, but par- delivery. They have great potential for tumor treatment
ticular biological features can make it a specific target for including hypoxia-responsive cargo release, prolonged
cancer therapy. In fact, tumor cells prefer aerobic glycol- blood circulation time, and enhanced tumor penetra-
ysis to obtain energy rather than the conventional oxidation and accumulation. Below we discuss the chemical
tive phosphorylation pathway due to the Warburg effect. structures that can be used to design effective hypoxia-
Therefore, many enzymes related to electron donation or responsive nanoparticles and the strategies for taking
reduction response are overgenerated in hypoxic tumor
Table 4 Hypoxia-selective chemical bond-triggered nanoplatforms

Type of chemical Therapeutic agent Therapy method Tumor model Refs.
bond
Nitro DOX/CP-NI NPs Chemotherapy, PDT Cervical carcinoma [505]

DOX@HMs Chemotherapy, RT Breast cancer [506]
DOX/FOBD liposome Chemotherapy Cervical cancer [507]
HRNP/siRNA Chemotherapy Breast cancer [286]
HC/PN/DOX NPs Chemotherapy, PDT Lung cancer [508]
NCs/DOX + Ce6 micelles Chemotherapy, PDT Breast cancer [509]
ALP-(MIs)n/DOX Chemotherapy, RT Glioma [510]
Gd-Au DENPs-Nit RT Nasopharyngeal carcinoma [511]
Azo DOX@AMOFs@ DRHC/CPPs Chemotherapy Breast cancer [306]
mPEG-AzoPAsp-IM micelles PDT Lewis lung carcinoma [294]
DOX@NP Chemotherapy Lung cancer [512]
CPs-CPT-Ce6 NPs Chemotherapy, PDT Cervical carcinoma [300]
PEG-Azo-PEI-DOPE Chemotherapy Cervical carcinoma [513]
CAGE Immunotherapy, PDT Melanoma [514]
ALN-HR-PMs/DOX Chemotherapy Prostate cancer [320]
N-oxide TPZ/UCSs Photodynamic/Chemo/ immuno- Colorectal cancer [515]
therapy
HAS-GOx-Fe3+-TA (HGTFT) Chemotherapy, CDT Breast cancer [516]
TENAB NPs Chemotherapy, PTT, PDT Cervical carcinoma [517]
Lip/Ce6/TPZ NPs Chemotherapy, PDT Breast cancer [518]
UiO-66-H-P NMOFs Chemotherapy, PDT Glioblastoma [519]
HA@AQ4N-Cu (II)-gossypol NPs Chemotherapy Prostatic cancer [520]
YS-DMONs-AQ4N- GOx Chemotherapy Prostatic cancer [326]
Mn-APPMSF Chemotherapy, PTT Hepatocellular carcinoma [521]
AQ4N-64Cu-hCe6- liposome Chemotherapy, PDT Breast cancer [325]
advantage of these nanoparticles for enhanced tumor Azobenzene (AZO) compounds

treatment. In hypoxic environments, AZO compounds can be
effectively reduced by NAD(P)H quinone dehydroge-
Hypoxia‑responsive drug delivery Nitro compounds nase 1 (NQO1) and azoreductase into two separate
In hypoxic cancer cells, the -NO2 group can be effec- aniline groups, rendering them suitable for preparing
tively converted into -NH2 via a series of biochemi- hypoxic-responsive nanoplatforms [286–288]. Moreo-
cal reactions involving NADPH and nitroreductase. It ver, matching the hypoxia-responsive features and the
should be noted that the first intermediate -NO can be broad absorption wavelength of the AZO groups with
reversely oxidized to the original -NO2 under normal the therapeutic bio-optical window can lead to more
conditions [277]. Based on the above bioreduction reac- efficient stimulus responses. Therefore, the AZO group
tions, polymers with -NO2 groups (such as 2-nitroimi- has been applied as an ideal linker allowing biologi-
dazole and nitrobenzyl alcohol) have been applied to cal rupture under appropriate hypoxic stimulus condi-
design hypoxic-responsive nanovehicles for the delivery tions [289–292]. For these hypoxic stimuli-responsive
of therapeutic agents. One significant profile of 2-nitro- nanoplatforms, the AZO groups are generally used to
imidazole is the conversion from a hydrophobic to hydro- link hydrophilic and hydrophobic moieties in amphiphi-
philic state after its reduction to 2-aminoimidazole in a lic molecules, which can self-assemble into nanoparti-
hypoxic environment. If functionalized with a hydro- cles under physiological conditions and disassemble to
philic block copolymer, the hydrophobic nitroimidazole release the loaded contents under hypoxic conditions by
groups can allow the block copolymer to form encapsu- breaking the AZO groups [293–297]. Therefore, break-
lated therapeutic agent nanocarriers through intermolec- age of the AZO linker can cause the cleavage of hydro-
ular hydrophobic interactions. However, the hydrophobic philic groups when the designed nanoparticles reach the
nitroimidazole groups can be effectively transformed into hypoxic tumor microenvironment, leading to enhanced
hydrophilic aminoimidazole groups, leading to disassem- cellular internalization and tumor accumulation of nano-
bly of nanocarriers and the release of loaded therapeutic particles [294, 298, 299]. For example, Zhang et al. [300]
agents in hypoxic tumor cells. For example, Thambi et al. synthesized a hypoxic-degradable nanocarrier func-
developed hypoxic-responsive nanoplatforms based on tionalized with AZO-containing hydrophobic groups
nitroimidazole-functionalized block co-polymers for to encapsulate the chemotherapeutic agent camptoth-
encapsulating and controlling the release of therapeu- ecin and photosensitive therapeutic agent chlorin e6 for
tic agents [280]. As expected, the cumulative release of laser-augmented synergistic chemo-photodynamic
therapeutic agents from the designed nanoplatforms was therapy. In this designed nanoplatform, chlorin e6-medi-
relatively slow under normoxic conditions but was obvi- ated PDT can exacerbate tumor hypoxia, allowing the
ously accelerated under hypoxic conditions. In addition hypoxia-responsive nanocarriers to rapidly disintegrate
to the transformation from a hydrophobic to a hydro- and release the encapsulated camptothecin. Continu-
philic. Currently, researchers have also developed other ous O2 consumption during PDT or SDT can mediate
strategies to take advantage of the hypoxia-sensitive an extremely hypoxic environment, giving potential for
potential of nitroimidazole [281–283]. Tseng et al. [284] the design of azoreductase-triggered nanoplatforms
reported bioreduction-responsive nanoplatforms func- acting in the local tumor region [301–304]. For exam-
tionalized with HA conjugated with 6-(2-nitroimidazole) ple, Zhang et al. [300] reported a versatile AZO-based
hexylamine to encapsulate lactate oxidase and a virus for nanoplatform resulting in a synergistic action of chemo-
use in tumor therapy. In this nanoparticle, lactate oxidase photodynamic therapy. Because of the O 2 consumption
can oxidize lactate resulting in O2 depletion inside tumor stimulated by PDT, Azo groups in the nanoparticles can
cells. Subsequently, bioreduction of the 2-nitroimidazole be effectively cleaved by overexpressed azoreductase to
of the nanocarriers converts it into a hydrophilic group trigger a faster release of chemotherapeutics in hypoxic
and dissociates the carrier backbones to release the anti- microenvironments. Using a similar strategy, Huang
cancer virus. Furthermore, Shi et al. [285] also designed et al. [305] developed smart supramolecular micelles to
a nanocarrier by co-assembly of 2-nitroimidazole-func- codeliver a photosensitizer and hypoxia-sensitive prod-
tionalized peptides and cationic lipid-like copolymers rug to enhance the antitumor effects. Satisfactory can-
for siRNA delivery to silence the expression of a hypoxia- cer cell killing in vitro and vivo demonstrated that the
relevant protumorigenic gene (CDC20) against breast designed micelles not only offered a new platform for the
cancer.
codelivery of therapeutic agents to tumors, but also pro- et al. designed a novel nanoplatform capable of regulat-
vided novel ideas for designing and preparing advanced ing the tumor microenvironment via Fenton reaction-
materials for multimodality tumor treatment. based chemodynamic therapy. This nanoplatform utilizes
Azoreductase-sensitive organic ligands can also be glucose-mediated continual O2 consumption to create a
used to construct nanoscale coordination complexes and localized hypoxic microenvironment for enhanced tira-
bring hypoxia-sensitive characteristics to nanothera- pazamine-mediated chemotherapy. The production of
nostics for tumor diagnosis and treatment. For example, exogenous H2O2 by GOx facilitates the release of Fe3+
Huang et al. [306] prepared an azoreductase-triggered from the nanoparticles to convert H2O2 into the highly
nanocomplex where the encapsulated chemotherapeu- cytotoxic ∙OH. This versatile nanoplatform showed
tic DOX and siRNA were capable of downregulating the enhanced tumor accumulation and excellent antitumor
expression of HIF-1α, thus reducing multidrug resist- efficacy in tumor-bearing models [318]. Yang et al. pre-
ance. 4,4′-Azobisbenzoinc acid, as the main ligand of pared nanoparticles capable of enhancing tumor hypoxic
the nanocomposites, was effectively reduced by azore- levels by loading vascular disruption agents that cut off
ductase to release the encapsulated DOX and siRNA the O2 supply. As a result, the designed nanoparticles
in the hypoxic tumor cells. In another example, Zhou not only suppressed tumor proliferation but also effec-
et al. [292] reported on an aptamer/antibody nanofor- tively inhibited tumor metastasis [319]. Moreover, PDT
mulation functionalized with hypoxia-sensitive AZO can be used as an excellent strategy to enhance tumor
compounds capable of decreasing off-target effects. In hypoxia and improve tirapazamine-mediated chemo-
this nanoformulation, a conditional aptamer was conju- therapeutic effects through the transformation of 3O2 to
1
gated with hydrophilic polymers containing AZO groups O2. For example, Yan et al. encapsulated tirapazamine
which played an important role in preventing binding into the pores of porphyrinic-based MOFs on the sur-
to normal cells. The hydrophilic block polymers could face of lanthanide-doped upconversion nanoparticles to
be detached from the nanoparticles through the reduc- prepare a versatile nanotheranostic agent. The cell and
tion of AZO, allowing aptamer/antibody recognition of animal experiment data showed that the combination
the cancer cell surface in a hypoxic microenvironment. of tirapazamine and PDT yielded enhanced therapeu-
Mesoporous silica nanoparticles are another important tic efficacy. Further, the integration of nanotheranostic
platform as inorganic drug delivery carriers for tumor agents with anti-programmed death-ligand 1 (anti-PD-
treatment. They have the advantages of low side effects, L1) clearly decreased the tumor volume at distant sites by
good biocompatibility and stability, relatively uniform improving immune infiltration [320].
size and a large specific surface area [307, 308]. For exam- Banoxantrone dihydrochloride (AQ4N) can not only be
ple, Jang and colleagues developed hybrid mesoporous selectively activated in hypoxic tumor cells but can also
silica nanoparticles functionalized with β-cyclodextrin be reduced under the action of reductases [321, 322]. The
and 4-(phenylazo) benzoic acid for improved on-demand protonated form (1,4-bis([2-(dimethylamino-N-oxide)
drug release. As expected, the nanoparticles displayed ethyl]amino)5,8-dihydroxy-anthracene-9,10-dine (AQ4)
improved selective drug release and significant cytotoxic- containing two tertiary amine groups) can utilize DNA
ity in comparison to nonresponsive nanoparticles [309]. intercalation to strongly suppress topoisomerase II [323,
324]. Thus, Feng et al. prepared a multipurpose liposome
Oxide groups to encapsulate soluble banoxantrone dihydrochloride and
The N-oxide group can also be used in the design and poorly soluble 64Cu-hCe6 into the cavity and lipid layer of
preparation of hypoxia-responsive nanoplatforms for the liposomes, respectively. Severe local hypoxia induced
effective tumor treatment [310]. Tirapazamine and ban- by Ce6 under laser irradiation could activate the antican-
oxantrone dihydrochloride are the most studied agents. cer activity of banoxantrone dihydrochloride, resulting in
Tirapazamine is an aromatic N-oxide compound while improved therapeutic efficacy in tumor-bearing models
banoxantrone dihydrochloride is an aliphatic N-oxide [325].
derivative, exhibiting higher cytotoxicity in hypoxic can- In another study, Yang et al. prepared novel organo-
cer cells than in normal cells [311–315]. silica nanoparticles containing tetrasulfide bonds to
In hypoxic tumor cells, tirapazamine can produce radi- encapsulate banoxantrone dihydrochloride and GOx for
cal species that break DNA through a single-electron tumor treatment [326]. Overexpressed GSH in tumor
reduction reaction catalyzed by various intracellular cells can effectively cleave the tetrasulfide bonds to dis-
reductases, leading to irreversible damage and apoptosis rupt the nanoparticles leading to the release of banox-
[316]. Because of the specific responsive strategy, nano- antrone dihydrochloride and GOx. Subsequently, GOx
particles that elevate tumor hypoxia can significantly can consume O 2 and glucose to produce H 2O2, thereby
enhance the antitumor effects of tirapazamine [317]. Guo exacerbating the hypoxia and further promoting the
transformation of banoxantrone dihydrochloride into novel hypoxia-sensitive nanoplatforms for enhanced

highly toxic AQ4. Furthermore, the consumption of tumor treatment.
GSH through the action of tetrasulfide bonds can greatly
enhance oxidative stress leading to tumor cell death. This Hypoxia‑responsive O2 release The effective delivery of
combinatorial strategy showed satisfactory in vivo and O2 to the tumor microenvironment shows great potential
in vitro results. in tumor therapy. Hyperbaric oxygen has been applied
The near-infrared fluorescence of banoxantrone dihy- to enhance the O2 concentration and reduce the side
drochloride also plays an important role in monitoring effects of hypoxia during radiotherapy [334, 335]. How-
therapeutic agent release and biodistribution for tumor ever, some adverse effects of hyperbaric oxygen, includ-
diagnosis and treatment. Shen et al. [327] prepared ing hyperoxic seizures and barotrauma, have limited its
multifunctional carrier-free nanoparticles loaded with clinical application [336–339]. Nanoparticles offer alter-
banoxantrone dihydrochloride to realize fluorescence natives for the precise delivery of O2 to the TME where
imaging-guided tumor treatment. There was no obvi- it can be effectively released and diffused into hypoxic
ous fluorescence when banoxantrone dihydrochloride lesions. Perfluorocarbon has been widely applied for the
was encapsulated into nanoparticles due to aggregation- construction of versatile nanoparticles that can carry O2
induced quenching. However, strong fluorescence was which it can dissolve. Song et al. [340] reported the sur-
observed after the collapse of the nanoparticles which face modification of nanoparticles with the radiosensi-
released banoxantrone dihydrochloride into the acidic tizer tantalum oxide (TaOx) and functionalization of the
tumor microenvironment. nanoplatforms with PEG. These designed nanoparticles
highly enhanced tumor cell oxygenation and solved the
Quinone compounds problems of RT in in vivo models. Hemoglobin, rich in
Quinone compounds and their derivatives have been red blood cells (RBCs), has been commonly applied as an
used in developing responsive tumor treatments because O2 carrier because of its excellent O 2-carrying capability
of their excellent electronic and chemical characteristics, [341–343]. For instance, Liu et al. [342] prepared versatile
particularly in hypoxia-activated prodrugs and fluores- nanoparticles engineered from recombined RBC mem-
cence imaging probes. Due to the particular redox poten- branes for the integration of hemoglobin and other thera-
tial properties of quinone compounds, they can produce peutic agents to enhance therapeutic efficacy. The extreme
semiquinones or hydroquinones via one or two-electron hypoxic microenvironment in tumor cells can effectively
reduction, respectively [328]. For example, the elimina- promote the release of O 2 from the designed nanoparti-
tion of indolequinones can be achieved under hypoxic cles. As expected, these nanoparticles significantly allevi-
environments with the aid of the DT-diaphorase NQO1, ated the hypoxic environment and enhanced the thera-
which is overexpressed in various cancer cells and plays a peutic efficacy. Overall, such chemical approaches can be
crucial role in bioreduction [329, 330]. Taking advantage used to design effective hypoxia-targeted nanoparticles
of this property, Tanabe et al. [331] designed 19F nuclear for enhanced tumor treatment.
magnetic resonance (NMR) monitor nanoprobes to
detect the biological reduction effects of indolequinones. Hypoxia‑mediated O2 production Enhancing O2 pro-
A single new signal was observed when the nanoprobes duction in the hypoxic tumor microenvironment has
were incubated with β-NADPH and NADPH-dependent been considered another important approach to address
cytochrome P450 reductase in hypoxic environments in problems with radio- and photodynamic therapy. Utiliz-
comparison to the preincubation groups. This hypoxic- ing the significant characteristics of the hypoxic tumor
responsive probe could become a valuable candidate microenvironment, including high redox potential and
for magnetic resonance imaging of cancers. In addition, acidic conditions, nanoplatforms can effectively produce
Jiho et al. reported on an enzyme-responsive prodrug O2 in situ by the catalysis of H2O2. This approach can be
generated by the chemical bonding of dopaquinone and divided into two categories: the utilization of the high
5-fluorodeoxyuridine. The results of in vitro assays dem- intracellular H2O2 levels in the hypoxic tumor microenvi-
onstrated that this prodrug increased the hypoxia target- ronment and the utilization of carrying groups to generate
ing capability of 5-fluorodeoxyuridine while significantly H2O2 locally. Metal nanoparticles are commonly applied
reducing the cytotoxicity to normal cells [332]. Cho et al. in catalysis [344, 345], imaging [346–348], and medi-
developed versatile nanocarriers functionalized with ben- cal applications [349, 350] because of their high specific
zoquinone groups [333] for the redox-responsive release surface area, nanoscale size and unique physicochemical
of therapeutic agents. Overall, there is clearly potential profiles. Under the acidic conditions of the hypoxic tumor
for using the unique characteristics of these compounds microenvironment, the catalytic ability of many metal
and their derivatives for the design and development of nanoparticles can be activated to transform H2O2 into O2
and H2O or hydroxyl radicals. Various theranostic nano- nanoparticles could also decompose water to generate
agents have been developed based on manganese (Mn) to O2 following laser irradiation, and subsequently trans-
induce Fenton-like reactions. form O2 into toxic 1O2 for tumor kill. The excellent pho-
Recently, Chen et al. designed an excellent TiO-porphy- tothermal conversion efficiency significantly enhanced
rin-based nanoplatform (FA-TiOPs) by loading TiO-por- blood circulation to the hypoxic tumor microenviron-
phyrin in FA-modified liposomes. These liposomes could ment. Additionally, Tang et al. designed a nanosensor for
effectively catalyze H 2O and overexpress H2O2, in situ the tracking and assessment of non-small cell lung can-
producing active ROS. Furthermore, TiO-porphyrin cer using near-infrared excited hypoxia imaging in which
could photo-split H 2O to generate H 2O2, ∙OH radicals, the acceptor and donor pairs within a biological MOF
and O2. The increased O2 concentration not only allevi- matrix are precisely controlled to rationalize upconver-
ated the hypoxic tumor microenvironment but could also sion Förster resonance energy transfer. It was found to be
be further converted by TiO-porphyrin into 1O2 to kill beneficial both in vitro and in in vivo zebrafish models.
cancer cells. Furthermore, researchers have reported that To overcome the limitations of hypoxia treatment
the high energy of TiO-porphyrin in the excited state and using photodynamic therapy, several radical generators
the narrow gap energy between the triplet excited state [354] that do not consume O2 have been developed. For
and the excited state may facilitate effective photocata- example, Dong et al. [355–357] have developed several
lytic reactions. In addition, overgenerated H2O2 in tumor advanced organic superoxide radical photo-generators
cells could also be catalyzed to produce 1O2, particu- to effectively address problems existing in hypoxia treat-
larly in an acidic environment, exerting active antitumor ment with PDT. In one instance, they formed highly
effects and preventing damage to healthy tissues. Overall, efficient photosensitizers to carry out type I PDT elimina-
tumor-targeted liposomes provided adequate ROS to the tion of hypoxic tumor tissues by vascular disruption. The
tumor through several in situ photocatalytic reactions in vitro and in vivo results showed that these nanopar-
that are O2 dependent and achieve effective cancer inhi- ticles could not only overcome the hypoxia paradox but
bition. Other therapeutic agents such as immunostimu- also suppress cancer metastasis through treatment with
latory or chemotherapy drugs can also be encapsulated type I PDT in 4TI breast cancer cell mouse models [355].
into such hypoxia-responsive nanoparticles through con- pH-sensitive zinc (II) metalated porphyrin nanoparti-
jugation or loading strategies for effective tumor-targeted cles were also prepared by this group to track and treat
therapy. cervical cancer tumor-bearing mice. Interestingly, they
observed that the phototherapy effects of the prepared
Other hypoxia‑responsive nanoplatforms With increas- nanoparticles could be effectively activated by increased
ing attention being paid to the hypoxic TME, a growing acidity [357]. Taken together, these hypoxia-responsive
number of strategies have been developed using external nanoparticles are making substantial progress in target-
stimuli, such as lasers. Xu et al. [351] designed an NIR ing tumor sites and enhancing therapeutic efficacy.
laser-controlled O2/Pt2+ self-producing prodrug (UCPP)
to enhance PDT efficacy in the hypoxic TME allow- Interstitial fluid pressure (IFP)‑related targeting strategies
ing combined photo-chemotherapy. The nanosystem The IFP in healthy tissues is only about 0–3 mm Hg,
included Pt4+ and Ce6, in which upconversion nanoparti- while tumors show an IFP of around 5–130 mm Hg [358].
cles were encapsulated to transform 980 nm near-infrared It should be noted that interstitial fibrosis and abnor-
light into 365 nm and 660 nm emissions to decompose mal lymph vessels and blood are considered the primary
Pt4+ and initiate Ce6-mediated PDT. The decomposition reasons for increased IFP [358, 359]. Elevated IFP can
of Pt4+ produced O 2 for depletion in the PDT process serve as an obstacle to the delivery of therapeutic agents,
and released Pt2+ for chemotherapy. Therefore, this novel because of drops in convection between the extravas-
nanosystem achieved enhanced tumor accumulation and cular and intravascular spaces, resulting in restricted
satisfactory tumor suppression in mouse xenograft mod- drug delivery to the tumor tissues. Further, it also cor-
els with no recurrence. relates with high recurrence rates in some tumors (such
Another emerging method is the use of lasers to as gynecological cancers) [360, 361]. Recently, some pre-
decompose abundant water molecules in living organ- liminary studies have reported that appropriate hyper-
isms to relieve hypoxic TME. Thus, Zheng et al. [352] thermia can effectively decrease intratumoral IFP to
prepared C3N4-based versatile nanoparticles to trigger facilitate tumor treatment. The intravenous administra-
the decomposition of H2O and produce O2 after expo- tion of chemotherapeutic agent-encapsulated liposomes
sure to 630 nm laser irradiation to reverse hypoxia- has been applied in combination with two ablative heat-
mediated PDT tolerance. In another example, Jiang et al. ing approaches to appropriate hyperthermia and coagu-
[353] reported that prepared ultrathin graphdiyne oxide lative ablation. For example, Zhao et al. reported that a
two-step ablation (45 ℃ for 2 min and 70 ℃ for 3 min) in mouse models [370]. Tang and co-workers prepared
conjunction with liposomes could obtain a survival ben- switchable aptamer micelle flares conjugated to a diacyl
efit in comparison to administering nanoformulations lipid chimera, which can monitor intracellular ATP [371].
with a single heating approach in a Balb/c mice bearing These micelles showed benefits for cell permeability and
4T1 tumor model [359]. Designing a versatile hyper- molecular imaging, with potential for tumor diagnosis
thermia therapeutic nanoparticle appears to provide a and targeted delivery. In summary, ATP can be consid-
promising potential approach for the improvement of the ered an efficient stimulus to promote release of preloaded
targeted drug delivery. drugs from nanoparticles for specific cancer treatments
and for diagnostic purposes
ATP‑responsive targeting strategies
ATP, which has been called “the energy currency of the Exogenous stimuli‑responsive targeting strategies
cell,” is fundamental to various cellular signal cascades.
ATP concentrations can reach up to 10 mM in tumor Temperature stimuli‑responsive targeting strategies
cells, while it is only approximately 5 mM in the extra- Temperature stimuli-responsive nanoplatforms have
cellular fluid. Therefore, a concentration gradient of ATP been designed for tumor treatment. Ideal tempera-
levels between extracellular and intracellular levels has ture-responsive materials with a lower critical solution
been used to develop ATP-responsive nanoplatforms for temperature include poly(2-oxazo line)s (POxs), poly-
tumor treatment. For instance, Kataoka’s group reported N-isopropylacrylamide (PNIPAAm), poly(methyl vinyl
ATP-responsive micelles for the delivery of siRNA to ether) (PMVE), and poly(vinyl caprolactam) (PNVCL),
tumors. Because of competitive binding between micelles which can readily undergo solid-to-liquid phase transi-
and ATP, the designed micelles could be crosslinked with tions according to external conditions [372–376]. Among
extracellular ATP but collapsed because of intracellular these materials, PNIPAAm has been most commonly
ATP, resulting in the efficient release of loaded siRNA used for preparing nanoplatforms as it has a lower critical
[362]. Aida et al. developed protein-based nanoplatforms solution temperature of approximately 30 ℃. As an exam-
to release ATP-sensitive agents for tumor treatment. ple, Grüll and co-workers prepared temperature stimuli-
The nanocarrier was prepared using various barrel- responsive liposomes loaded with therapeutic agents for
shaped chaperonin groups assembled via coordination high intensity focused ultrasound-mediated targeted
with Mg2+ into tubular structures that protected loaded delivery. As expected, temperature stimuli-responsive
therapeutic agents from biological metabolism and deg- release of cargoes was observed along with enhanced
radation [363]. Upon internalization by tumor cells, endocytosis of therapeutic agents by the tumor cells
hydrolysis of ATP to form ADP can trigger protein con- [377]. In another example, Deng et al. prepared DOX-
formational changes and collapse of the nanoparticles, encapsulated temperature stimuli-responsive liposomes
resulting in the selective release of the contents [363]. surface functionalized with iRGD peptide (CCRGDKG-
ATP ligands have been developed for monitoring ATP PDC) for targeted tumor treatment. In combination with
using several sensors, including electrochemical, colori- high intensity focused ultrasound-mediated temperature
metric, and fluorescent platforms [364–368]. Wang et al. stimuli-responsive DOX release, the designed liposomes
prepared nanoparticles complexed with PEI hybridized were specifically internalized by αvβ3-positive tumor
with the ATP-responsive ligands, siRNA and DOX. The cells, with good treatment efficacy [378]. As explained
prepared nanoparticles using a gradient of ATP concen- above, temperature stimuli-responsive nanoparticles
trations showed rapid cargo release in an ATP-respon- can have a significant impact at the cellular level, which
sive manner. An enhanced anti-proliferative effect was potentiates the cytotoxicity of certain active pharma-
observed, possibly due to enhanced cell apoptosis in ceutical ingredients, mostly explained by changes in
mitochondria-mediated pathways and cell cycle arrest the pharmacokinetics of the agent under hyperthermic
at the G2 phase [369]. In another example, Gu et al. conditions and associated cellular changes, resulting in
designed ATP-binding aptamer DNA functionalized increased nanoparticle uptake.
with polymeric nanocarriers encapsulated with chemo-
therapeutics for targeted delivery to ATP overgenerated Magnetic stimuli‑responsive targeting strategies
environments. In comparison to non-ATP responsive Over the past few decades, magnetic stim [379–381].
nanogels, the ATP-responsive nanogels achieved sig- Moreover, considering that magnetic nanoparticles have
nificant therapeutic effects in various tumor cell lines. excellent physiochemical performances and biological
Furthermore, functionalization with hyaluronic acid for effects, they have been proposed as ideal platforms for a
tumor-specific targeting accompanied by ATP respon- number of tumor theranostics [382]. Encapsulated super-
siveness improved tumor inhibition in tumor-bearing paramagnetic Fe2O3 nanoparticles (SPIONs) present an
excellent magnetic moment and satisfactory biocompat- guided by ultrasound stimuli. Under ultrasound treat-
ibility in comparison to other magnetic stimuli-respon- ment, the designed nanoparticles exhibited satisfactory
sive nanoplatforms. Furthermore, magnetic molybdenum drug release, cellular uptake and other pharmacokinetic
disulfide (mMoS2) can be modified by liposomes with a characteristics, as well as superior antitumor efficacy in
phospholipid bilayer membrane structure to construct glioma models [392]. Zheng’s group prepared ultrasound
magnetically responsive nanoplatforms which do not stimuli-responsive DOX-loaded mesoporous silica nano-
easily aggregate in physiological solutions, and have particles featuring the ultrasound-responsive release of
good biocompatibility, thereby showing great promise for cargoes for glioma treatment. They showed an obvious
nanomedicine applications [383]. suppression in tumor invasiveness and growth, as well as
Successful application of magnetically responsive nan- increased survival in a mouse glioma model [393]. Mura-
oplatforms includes encapsulation/immobilization of gaki’s group developed epirubicin-encapsulated micelles
therapeutic agents into magnetic-responsive nanoplat- as tumor sonosensitizers. Using HIFU, the nanoparticles
forms, injection of the magnetic stimuli-responsive nano- could be disrupted to allow drug release in canine spon-
platforms into the body and taking advantage of external taneous chondrosarcoma, osteosarcoma, hepatocellular
magnetic fields to recruit and activate the magnetic stim- and prostate cancer [394]. Biocompatible piezoelectric
uli-responsive nanoplatforms at the lesions of interest nanoparticles have also been encapsulated with DSPE-
[384–386]. Recently, Shuai et al. [387] reported a GSH- PEG and modified with anti-HER2 Ab for targeted breast
responsive MOF to effectively load IDO inhibitor, and cancer treatment. As anticipated, these designed ultra-
NO donor s-nitrosothiol groups for improving antitumor sound stimuli-responsive nanoplatforms can effectively
immunotherapy. In this nanoplatform, the high T1 relax- release encapsulated active pharmaceutical ingredients
ivity endows magnetic resonance (MR) imaging capabili- in a controlled manner, interfering with cell division and
ties to detect the in vivo biodistribution of nanoagents. inhibiting tumor proliferation
Shi et al. reported a versatile nanodiagnostic based on
DOX-encapsulated tannic acid-Fe networks (TAFs) Laser stimuli‑responsive targeting strategies
functionalized with fibronectin for combination cancer Laser stimuli can break light-sensitive functional bonds
treatment under the guidance of MR imaging. In this sys- or groups, including coumarinyl ester, truxylic acid and
tem, the TAF network allows the nanodiagnostic to have pyrenyl methyl ester. Much work has focused on employ-
excellent r1 relaxivity for T1-weighted MR cancer imaging these laser-responsive nanoplatforms to deliver
ing [388]. The development of magnetic stimuli-respon- chemotherapeutic agents by destroying the nanovehi-
sive nanoparticles with imaging properties will help to cle at the lesions [395–399]. For example, Chen et al.
determine when there is good tumor accumulation. prepared a photolabile spherical nucleic acid for light-
responsive codelivery of antisense oligonucleotide and
Ultrasound stimuli‑responsive targeting strategies siRNA. Upon exposure to an NIR laser, the prepared
Ultrasound has become an excellent external stimu- nanoplatforms rapidly oxidized and dissociated with con-
lus capable of facilitating the disruption of nanoparti- tinuous responsive release, resulting in a positive effect
cles and releasing their cargoes at the lesions of interest on tumor treatment [400]. Xu et al. designed a light stim-
[389]. Ultrasound stimuli-responsive nanoplatforms can uli-responsive nanoparticle to achieve long blood circu-
therefore be a valuable tool for enhancing therapeutic lation, enhanced tumor accumulation and penetration,
agent accumulation in tumors with low EPR effects. For and rapid body elimination in an imaging-guided treat-
example, SDT-based nanoparticles capable of continu- ment. After the nanoplatform accumulated in the tumor
ous production of CO2 have been recently developed to regions, the cargoes could be effectively released by laser
accomplish ultrasound-mediated inertial cavitation irradiation. Importantly, the released therapeutic agents
(UIC) to augment ROS accumulation against cancer could effectively penetrate the whole tumor tissue with a
[390]. The in vitro and vivo results indicated that con- diameter of approximately nine millimeters giving tumor
tinuous UIC accelerated a massive generation of ROS, suppression [401]. Additionally, Kim’s group prepared a
resulting in the improvement of SDT using a single laser-responsive and biomimetic nanoplatform for deep
nanoplatform. Furthermore, the highly-accumulative tumor penetration [402]. In this study, the in vitro drug
ROS arising from continuous UIC have been shown to release profile and tumor cell inhibition rate were signifi-
induce robust immunogenic cell death (ICD), which is cantly improved after laser irradiation. The use of lasers
typically represented by increased antigen exposure and as an exogenous stimulus can effectively improve the
presentation, enhanced DC maturation and more acti- therapeutic effect and reduce the side effects by control-
vated CD8+T cell infiltration in tumors [391]. Price et al. ling the drug release behavior.
prepared cisplatin encapsulated solid lipid nanoparticles
Hybridization and combination of cancer these stimuli will be employed to load the drug into the
nanomedicine nanoparticles and trigger the drug release. Additionally,
Designing smart targeting nanoparticles with stimuli- the activation of drug release under external stimuli,
responsive profiles has proved promising for providing including a magnetic field, temperature, light or ultra-
site-specific, accurate, and systemic drug administra- sound, can also be achieved at the targeted site. Owing
tion. Moreover, stimuli-responsiveness can substantially to the complex TME, including the abnormal expression
increase the diverse utility of such systems by integrating of multiple receptors, high redox potential, and abnor-
drug administration with other features, such as sensing, mal metabolic conditions, smart nanoparticles have been
imaging, or monitoring. The designed smart nanoparti- specially developed for anticancer medication. Studies
cles can accumulate in the tumor region through either using stimuli-responsiveness and targeting strategies are
passive targeting behavior (EPR effects) or receptor- detailed in Table 5.
mediated active targeting strategies. Subsequently, such For example, a smart dual-responsive and target-
nanoparticles provide yet another possibility to fine tune ing nanoplatform was prepared for the codelivery of
their response toward each stimulus individually, ena- chemotherapeutics (DOX and PTX) for treatment of
bling drug release to be precisely controlled under the lung adenocarcinoma [403] (Fig. 7). In this nanoplat-
cumulative effect of multiple stimuli. In these nanopar- form, FA was used as a receptor-mediated targeting mol-
ticles, multiple impulses are integrated to activate nano- ecule to facilitate the entry of these nanoplatforms into
particles in the TME by introducing exogenous stimuli, tumor cells. Moreover, acid-liable block copolymers and
such as laser and ultrasound. In such systems, one of disulfide bonds endowed the nanoplatform with pH and
Table 5 The hybridization and combination of cancer nanomedicine

Targeting strategy Stimuli-responsiveness Therapeutic agent Tumor type Refs
FA pH PEG-FA/(DOX + VER)@ZIF-8 Melanoma [522]

GSH FA-S–S-PLGA NPs Lung cancer [523]
ROS Lut/FA-Oxi-αCD NPs Breast cancer [524]
MMP2 F/TMSP-NLC Fibrosarcoma [525]
pH and GSH PsEEL-DOX/PTX NMs Lung cancer [403]
pH and ROS DT-NP Breast cancer [527]
pH and laser HM-Bi@PEG-FA NSs Lung cancer [528]
HA GSH HL/MOS@M780&LOD NPs Breast cancer [526]
pH HA/(R837 + 1 MT)@ZIF-8 Melanoma [529]
Laser DOX/ICG-CuS@MnO2/HA NPs Breast cancer [530]
pH and GSH DOX/siGCN5@HPMSNs Breast cancer [531]
GSH and hypoxia PaHAsC Melanoma [91]
RGD GSH RGD/MoS2/DOX Cervical cancer [532]
pH Met/GOx@His/ZIF-8∼RGD Breast cancer [533]
MMP-2 RHMH18@AuD NPs Ovarian cancer [534]
Laser SPIOCs@HSA(PTX)-RGD Glioma [535]
pH and esterase IR825@IRI-ATRA/RGD NPs Breast cancer [536]
pH and GSH CuS DENPs Breast cancer [537]
Biotin pH B780/Qu NPs Breast cancer [98]
GSH SS-biotin-Ppy NWs Breast cancer [538]
Transferrin Temperature TMNP Breast cancer [80]
GSH DMSN@PMAsh-Tf Lung cancer [539]
pH/temperature LF-PNIPAM-co-AA Breast cancer [540]
LHRH GSH PTX-LHRH-DCMs Breast cancer [97]
pH, HIFU, and ultrasound LHRH-ELP-DOX Breast cancer [541]
EPR effects pH and cathepsin B TNV Melanoma and colon [250]
cancer
P2, pH and ROS SRF/Ce6-loaded PEG-M-PPMT NPs Lung cancer [542]
RGD and EPR effects Laser and GSH RDG/shRNA Breast cancer [543]
Fig. 7 Schematic illustration of stimuli-responsive and targeted nanoplatforms for the specific delivery of therapeutic agents. A Preparation
of the smart nanoplatform via electrostatic and hydrophobic interaction, and the pH-responsive surface charge switch, and GSH-responsive
chemical degradation of polymer backbone. B Schematic illustration of and FA-mediated target and pH/GSH-responsive delivery processes:
(a) the nanoplatforms show high stability in blood circulation; (b) therefore, they can effectively accumulate in tumor lesions via the EPR effect
and receptor-mediated targeting; (c) acidic conditions can cause charge conversion of the nanoplatform; (d) endosome escape of the smart
nanoplatform via proton-sponge effect; (e) intracellular GSH stimulation will trigger the release of therapeutic agents for tumor treatment
GSH-responsive drug release behavior in the TME. It nanoplatform showed good biocompatibility, excellent
should be noted that the prepared nanoplatforms exhib- cellular internalization, and improved tumor cell inhibi-
ited a surface charge switch from negative to positive tion. Furthermore, the nanoplatform appeared synergis-
during transmission from physiological environment to tic and improved solid tumor killing efficiency compared
the TME, which can enhance tumor cells internalization. with mono-chemotherapy in tumor-bearing mice mod-
Subsequently, endosome escape of the nanoplatforms els. This suggests that hybridization and combination of
was achieved in the acidic endo/lysosome environment cancer nanomedicines present great promise for tumor
via the "proton-sponge" effect. As expected, this smart treatment. In another important example, Jeong Hoon
Byeon’s group [404] developed a platform for digitiz- their physiological environment. For example, most car-
able and continuous-flow manufacture in a compact bon nanomaterials (such as carbon nanoparticles and
and reconfigurable manner using a serial combination of nanotubes) and metals (such as MnO) can act efficiently
plug-in reactionwares. This platform comprised three dif- in acidic environments but generate ROS near tumors
ferent composite nanocompounds with photothermally which can lead to cancer progression and metastasis
modulatable and structurally degradable characteris- [410, 411]. Notably, ROS-responsive nanoplatforms tend
tics for cancer treatment. As expected, these nanocom- to be rapidly phagocytized due to their special surface
pounds used for NIR-triggered chemothermal cancer properties [412, 413].
therapy showed excellent anticancer efficacy with low In the future, there is an urgent need to control the
side effects and effective renal excretion. Taken together, physicochemical features of nanoparticles to improve
the hybridization and combination of nanomedicine their targeting ability, especially their morphology, parti-
appears to hold great promise for cancer treatment. cle size distribution and surface chemistry. For example,
new surface modification strategies need to be explored
Conclusions and prospects to confer novel multifunctionalities to the nanoparticles.
In this review, we have focused on recent advances in Moreover, in order to improve the antitumor effects of
receptor-mediated and stimuli-responsive active tar- nanoparticles the development of alternative reactions,
geting strategies for cancer treatment. These versatile formulations, or constructs containing stimulus compo-
nanoparticles effectively overcome undirected drug bio- nents aimed at producing multiple strategies for highly
distribution, undesired toxicity and high doses of admin- effective combination cancer treatment should be a
istration, and play an important role in the development focus. Importantly, these new generation targeting strat-
of novel chemotherapeutic agents and the understand- egies should be explored for an in-depth understanding
ing of their antitumor efficacy. Significant progress has of key parameters, such as their pharmacokinetics, bio-
been made in developing target-specific therapies lead- distribution and nano-bio interfacial interactions, as such
ing to better cellular internalization and site-specific outcomes have a significant impact on cancer treatment.
agent release by exploiting specific cancer cell surface Furthermore, there are possibilities to develop novel
receptors. These active targeting strategies not only stimuli-responsive modalities for better encapsulation
enhance the efficacy of the drug but also reduce poten- of agents as well as their controlled release to further
tial side effects. Additionally, stimuli-responsive target- increase their therapeutic index with few side effects. It
ing strategies with their unique characteristics have also is forecast that nanoscale biomaterials comprising bio-
shown high stability, enhanced tumor accumulation, compatible lipids, polymers or inorganic materials in
and rapid release behaviors in response to exogenous conjugation with targeting groups will have tremendous
or endogenous environmental stimuli both in vitro and scope for transporting pharmaceutical active ingredi-
in vivo. Taken together, precise delivery and specific ents to their specific target sites for improved therapeutic
release can be readily achieved by using the synergistic purposes. Such versatile targeted nanoparticles will find
effects between versatile receptor-mediated and stimulus broader application possibilities and will aid in the role
response targeting strategies, resulting in killing cancer out of personalized/precision medicine.
cells within the tumor without damaging healthy tissues.
While the abovementioned approaches have many ben-
Abbreviations
efits, there are also some caveats. The size and surface EPR: Enhanced permeability and retention; HA: Hyaluronic acid; TME: Tumor
characteristics of nanoplatforms can disrupt membranes microenvironment; FRs: Folate receptors; Tf: Transferrin; FA: Folate acid; EGFRs:
and interfere with protein folding and membrane activ- Epidermal growth factor receptors; HER2: Human epidermal growth factor
receptor 2; DOX: Doxorubicin; PTX: Paclitaxel; TGF-α: Transforming growth
ity. These intracellular dysfunctions can further trigger factor-α; IFP: Interstitial fluid pressure; MOF: Metal organic framework; UIC:
feedback mechanisms such as “frustrated phagocytosis” Ultrasound-mediated inertial cavitation; POxs: Poly(2-oxazo line)s; PMVE: Poly
[405]. Once administrated, the prepared nanoplatforms (methyl vinyl ether); NMR: Nuclear magnetic resonance; GOx: Glucose oxidase;
AZO: Azobenzene; Ce6: Chlorin e6; NQO1: NAD(P)H quinone dehydrogenase
circulate in the bloodstream to access various tissues 1; GSH: Glutathione; PEG: Polyethylene glycol; CA IX: Carbonic anhydrase IX;
or organs. During this circulation, these nanoplatforms Ab: Antibody; ATP: Adenosine triphosphate; TZ: Trastuzumab; PTT: Photo-
can interact with biomacromolecules (including carbo- thermal therapy; PDT: Photodynamic therapy; CDT: Chemodynamic therapy;
RT: Radiotherapy; CAT: Catalase; ROS: Reactive oxygen species; RNS: Reactive
hydrates, proteins, nucleic acids, and lipids) which can nitrogen species; MR: Magnetic resonance; MMP: Matrix metalloproteinase;
coat the nanoplatforms, leading to a surface or biomol- TaOx: Tantalum oxide; RBCs: Red blood cells; ICD: Immunogenic cell death;
ecule corona, which alters the surface properties of the PNIPAAm: Poly-N-isopropylacrylamide; PNVCL: Poly(vinyl caprolactam); PK: Pro-
tein kinase; ICP-OES: Inductively coupled plasma optical emission spectrome-
nanoplatforms, affects their therapeutic effects, and can try; CD: Cluster of differentiation; ECM: Extracellular matrix; CPT: Camptothecin;
induce protein unfolding [406–409]. Stimuli-responsive DOTAP: 1,2-Dioleoyl-3-trimethylammonium-propane; AQ4N: Banoxantrone
nanoplatforms are effective but can still be affected by dihydrochloride; DTD: DT-diaphorase; TKIs: Tyrosine kinase inhibitors.
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Competing interests tional theranostic nanoparticles based on exceedingly small magnetic
The authors declared that they have no competing interests. iron oxide nanoparticles for T-weighted magnetic resonance imaging
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1
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Enhancing The Therapeutic Efficacy of Nanoparticles For Cancer Treatment Using Versatile Targeted Strategies

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Tian et al.

Journal of Hematology & Oncology (2022) 15:132

REVIEW Open Access

Enhancing the therapeutic efficacy

Background an urgent need for site-specific delivery of therapeutic

nanoparticles also overcome many of the disadvantages

Receptor‑mediated active targeting strategy

Fig. 3 Schematic representation of receptor-mediated endocytosis

tion (50 – 100 Μm) is not sufficient to generate adequate

Table 2 ROS-responsive building blocks for cancer treatment

Thioketal linker Polyprodrug ­NPDOX/Cy Breast cancer Chemotherapy [493]

Table 3 pH-responsive building blocks for tumor treatment

Poly(2-(hexamethyleneimino)ethyl methacrylate siBRD4-loaded TCPA2-NPs Prostatic cancer LNCaP-bearing mouse GT [477]

Table 4 Hypoxia-selective chemical bond-triggered nanoplatforms

Nitro DOX/CP-NI NPs Chemotherapy, PDT Cervical carcinoma [505]

advantage of these nanoparticles for enhanced tumor Azobenzene (AZO) compounds

transformation of banoxantrone dihydrochloride into novel hypoxia-sensitive nanoplatforms for enhanced

Table 5 The hybridization and combination of cancer nanomedicine

FA pH PEG-FA/(DOX + VER)@ZIF-8 Melanoma [522]

Acknowledgements PEGylated nanocarriers for cancer immunochemotherapy. J Control

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Thioketal linker Polyprodrug NPDOX/Cy Breast cancer Chemotherapy [493]