Biomedicine & Pharmacotherapy 173 (2024) 116330

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Traditional Chinese medicine polysaccharide in nano-drug delivery

systems: Current progress and future perspectives
Juan Wang a, 1, Xia Wu a, 1, Jing Chen b, Ting Gao b, Yumei Zhang a, c, *, Na Yu b, d, **
a
Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, China
b
Department of Pharmaceutical Preparation, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
c
Department of Chemistry, School of Basic Medical Science, Ningxia Medical University, Yinchuan, Ningxia, China
d
Department of Clinical Pharmacology, School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, China

A R T I C L E I N F O A B S T R A C T

Keywords: Traditional Chinese medicine polysaccharides (TCMPs) have gained increasing attention in the field of nano­
Traditional Chinese medicine polysaccharide medicine due to their diverse biological activities and favorable characteristics as drug carriers, including
Nano-drug delivery system biocompatibility, biodegradability, safety, and ease of modification. TCMPs-based nano-drug delivery systems
Reticuloendothelial system
(NDDSs) offer several advantages, such as evasion of reticuloendothelial system (RES) phagocytosis, protection
Construction strategies
against biomolecule degradation, enhanced drug bioavailability, and potent therapeutic effects. Therefore, a
comprehensive review of the latest developments in TCMPs-based NDDSs and their applications in disease
therapy is of great significance. This review provides an overview of the structural characteristics and biological
activities of TCMPs relevant to carrier design, the strategies employed for constructing TCMPs-based NDDSs, and
the versatile role of TCMPs in these systems. Additionally, current challenges and future prospects of TCMPs in
NDDSs are discussed, aiming to provide valuable insights for future research and clinical translation.

1. Introduction hinder the efficient delivery of nanodrugs to target organs [10,11].

Additionally, NDDSs are susceptible to reticuloendothelial clearance
Nanotechnology has revolutionized the field of medicine and and often exhibit insufficient tumor penetration [12]. The effectiveness
healthcare [1,2]. Nanodrug delivery systems (NDDSs) represent a spe­ of NDDSs is closely linked to the properties of the carrier material. While
cific application of nanotechnology and play a central role in the prog­ early NDDSs predominantly utilized artificially synthesized materials,
ress of nanomedicine [3]. Over the past decades, NDDSs have been there is a growing need for innovative polymeric biomaterials that can
extensively studied for the prevention and treatment of various diseases, overcome these challenges and facilitate scale-up and clinical trans­
particularly cancer and infections, due to their numerous advantageous lation [13,14]. Consequently, extensive efforts have been directed to­
features [4,5]. These features include efficient encapsulation of insol­ wards developing novel biomaterials that effectively address biological
uble pharmaceuticals in aqueous systems, protection of drugs against barriers, clearance issues, and limited tissue penetration [12].
chemical or enzymatic degradation [6], and prolonged blood circulation The emergence of traditional Chinese medicine polysaccharides
resulting from reduced elimination [7]. In cancer therapy, NDDSs can (TCMPs) presents a promising solution to these challenges. TCMPs are
accumulate at tumor sites through passive or active targeting using biopolymers derived and purified from traditional Chinese medicine
bio-specific ligands [8]. Moreover, NDDSs enable controlled drug (TCM) sources, offering biodegradability and serving as potent sub­
release and can overcome multidrug resistance (MDR) in cancer cells, stances for various medical treatments [15]. Moreover, TCMPs exhibit
making them promising strategies for chemotherapeutic drug delivery exceptional biocompatibility and safety due to their biochemical
[9]. However, the utilization of NDDSs faces significant challenges. resemblance to the extracellular matrix (ECM) of human tissues [16].
Biological barriers, such as intravascular enzymes, mononuclear Consequently, TCMPs have gained momentum in pharmaceutical
phagocyte sequestration, endothelial barriers, and plasma membranes, preparations over the past five years. It is noteworthy that TCMPs have

* Correspondence to: Department of Pharmaceutics, College of Pharmacy, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan 750004, China.
** Correspondence to: Department of Pharmaceutical Preparation, General Hospital of Ningxia Medical University, Yinchuan 750004, China.
E-mail addresses: [email protected] (Y. Zhang), [email protected] (N. Yu).
1
These authors contributed equally to this work and shared first authorship.

https://doi.org/10.1016/j.biopha.2024.116330
Received 16 November 2023; Received in revised form 19 January 2024; Accepted 22 February 2024
Available online 28 February 2024
0753-3322/© 2024 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC license
(http://creativecommons.org/licenses/by-nc/4.0/).
J. Wang et al. Biomedicine & Pharmacotherapy 173 (2024) 116330

the potential to prolong drug retention in the body [17], evade recog­ mannose, galactose, rhamnose, arabinose, and xylose [28]. These
nition and clearance by the reticuloendothelial system (RES) [18], and monosaccharides contribute to the abundance of functional groups, such
provide cell surface recognition sites to enhance drug accumulation at as hydroxyl, carboxyl, and amino groups, within the structure of TCMPs.
the target site [19]. These characteristics indicate the untapped poten­ Consequently, their structural modification, such as sulfation of LBP
tial of TCMPs in overcoming the challenges faced by NDDSs in clinical [29], carboxymethylation of GLP and ASP [30,31], and selenium
applications, particularly in cancer therapy. modification of GP [32], becomes feasible. These modifications not only
Furthermore, the flexibility of TCMPs design and modification en­ alter the physicochemical properties of TCMPs but also significantly
ables the production of tailored derivatives with specific qualities, such enhance their biological activity [33,34]. The inherent structural flexi­
as hydrophobicity and solubility. This expands the utilization of TCMPs bility, combined with their high biocompatibility and biodegradability,
in various application areas [20–22]. Notably, TCMPs possess diverse renders TCMPs attractive excipients for nanodrug delivery systems
pharmacological activities, including antitumor and immunomodula­ (NDDSs). It has been suggested that the physicochemical properties and
tory effects [23,24]. Hence, they can serve not only as drug delivery bioactivities of TCMPs are closely linked to their structure, indicating
carriers but also as adjuvant bioactive components and tumor-targeting their potential for diverse applications [35]. To date, several TCMPs,
ligands in NDDSs. Recent studies in cancer nanomedicine have explored including Angelica polysaccharides (ASP), Astragalus polysaccharides
the use of TCMPs as tumor-targeting ligands to improve the precision of (APS), Ganoderma lucidum polysaccharides (GLP), Bletilla poly­
drug delivery [25–27], opening new avenues for research on TCMPs in saccharides (BSP), Auricularia auricular polysaccharides (AAP), Len­
NDDSs. Building upon these groundbreaking studies, this review aims to tinan (LNT), Laminarin polysaccharides (LP), Glycyrrhiza
describe the characteristics of TCMPs used in NDDSs, highlight strate­ polysaccharides (GP), Codonopsis ginseng polysaccharide (CGP), Chi­
gies for constructing NDDSs based on TCMPs, provide an overview of nese yam polysaccharide (CYP), Radix pseudostellariae polysaccharides
various types of TCM-based NDDSs, and emphasize the advantages of (RPP), and Lycium barbarum polysaccharides (LBP), have been
polysaccharide-based NDDSs. Finally, practical applications of NDDSs employed in the development of NDDSs. This review summarizes the
based on TCMPs will be discussed. diverse range of structural characteristics and biological activities of
TCMPs due to their complex composition.
2. The structural characteristics and biological activities
2.1. Structural features
TCMPs are biologically derived macromolecular polymers composed
of more than ten monosaccharide units linked by glycosidic linkages. The structural features of TCMPs primarily involve monosaccharide
The primary monosaccharides present in TCMPs include glucose, composition, molecular weight (MW), glucoside bond location and

Table 1
The structural characteristics and biological activities of TCMPs.
Polysaccharide types Monosaccharide Molecular Structures Biological activity References
composition (molar ratio) weight

Astragalus Rha: Xyl: Glc: Gal: Man: 8.7–4800 kDa α -(1→4)-D-glucan, with a single α-D-Glc at Immunomodulation,anti-oxidant, anti- [36]
polysaccharides Fru= 4.9: the C-6 position every nine residue tumor, anti-diabetes, anti-viral,
(APS) 4.7: 8.3: 122.2: 2.2: 3.1 hepatoprotection, anti-inflammation, anti-
atherosclerosis, hematopoiesis and
neuroprotection.
Lycium barbarum Ara: Rha: Xyl: Man: Gal: 241 kDa →6)-β-Galp (1→, α-Araf, β-Galp,α-Rhap Immunomodulatory, anti-oxidant, [40]
polysaccharides Glc =0.18: 0.81: 0.07: prebiotic, anti-tumor, and hypoglycemic.
(LBP) 2.17: 0.23: 6.52
Angelica Sinensis Glc: Gal: Ara= 3.7: 1.0: 16.1 kDa →6)-α-Glcp-(1→6)-α-Glcp-(1→5)-α-Araf- Gastrointestinal protective, immune- [41]
polysaccharides 2.1 (1→5)-α-Araf-(1→3,5)-α-Araf-(1→3)- modulatory, anti-tumor, anti-inflammatory,
(ASP) β-Galp-(1→3)-β-Galp-(1→4)-α-Galp- anti-oxidant, hematopoietic,
(1→3)-α-Araf-(1→3,5)-α-Araf-(1→ hepatoprotective, and radioprotective.
Ganoderma lucidum Glu: Gal: Man: Xyl: Fuc: 37 kDa 1,3-linked-β-D-Glcp with 1–15 units of 1,6- Anti-tumour, immune-modulatory, [42–44]
polysaccharides Rha= 5.35: 2.67: 1: 1.19: linked-β-D-Glcp side chains anti-oxidant, hypoglycaemic.
(GLP) 0.38: 0.37
Bletilla Man: Glu = 3:1 100–130 kDA 1,4-linked mannosyl residues and 1,4- Promote prothrombin, anti-inflammatory, [45]
polysaccharides linked glucosyl residues anti-oxidation, promote wound healing,
(BSP) anti-tumor, and immunomodulation.
Auricularia auricular Xyl: Man: Gal: Glu/ 500 kDA D-mannopyranosyl residue and the side Anti-coagulant, anti-tumor, anti-oxidation [46]
polysaccharides glucuronic acid= chain of β-D-xylose and immune activities.
(AAP) (1.8:75.6:1.7:21.1)
Lentinan (LNT) Glu: Man: Gal =19.26: 379 kDA β-(1→3)-glucan backbone with-(1→6)- Anti-tumor, anti-oxidative, anti- [47]
1.20: 1.00 glucosyl side-branching units terminated inflammatory, anti-bacterial and anti-viral.
by mannosyl and galactosyl residues
Laminarin Glc 8.4 kDa non-reducing glucopyranosyl (t-Glcp), / [48]
polysaccharides (1→3)-Glcp,
(LP) and (1→3, 6)-Glcp residues
Glycyrrhiza Ara: Rha: Gal: Glc: Man 289 kDa →(6)-β-D-Glcp-(→trunk and→4)-α-D-Xylp- Anti-oxidation, immune regulation, anti- [49]
polysaccharides =1.08: 1.25: 3.01: 5.85 (1→, →5)-α-l-Araf-(1→, →3)-α-l-Rhap- tumor, apoptosis, anti-microbial, and anti-
(GP) (1→, →6)-α-D-Galp-(1→, →3, 6)-α-Manp- inflammation
(1→and→1)-β-D-Glcp as a branch. The
main chain of Glycyrrhiza glabra
polysaccharide were found to be 1, 4-linked
Glcp, T-linked Glcp,1, 4, 6-linked Glcp,and
1, 6-Connected Glcp
Radix / / / Immunomodulation, appetite, nourishing [50]
pseudostellariae vitality, and moistening lung
polysaccharides
(RPP)

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polymerization degree [36]. Features of currently reported TCMPs are Table 2

summarized in Table 1. Among these TCMPs, LBP consist of seven pharmacological mechanism of TCMPs.
monosaccharides: galactose (Gal), glucose (Glc), fucose (Fuc), arabinose Pharmacological TCMPs The mechanism of action References
(Ara), mannose (Man), rhamnose (Rha), and xylose (Xyl), with an activities
average MW of 10–400 kDa [37]. APS has a MW range of 8.7–4800 kDa, Immunomodulatory LBP Enhance the phagocytosis of [51–53]
including one terminal Ara, one 1,5-linked Ara, one 1,3-linked Rha, one activity macrophages and promote
1,3,4-linked Rha, six 1,4-linked glucuronic acid (GlcA) and five 1, the proliferation of dendritic
4-linked galacturonic acid (GalA) residues [36]. Most mono­ cells
GLP Interact with dectin-1, Toll- [54]
saccharides found in GLP are heteropolysaccharides with linear or like receptors (TLRs), or
branching molecules, and their molecular weight ranging from 2 to mannose receptors (MR) on
800 kDa [38]. BSP contains Man, Glu, and Gal in a molar ratio of mononuclear phagocytes and
9.4:2.6:1.0, with a molecular weight of 2.35 × 105 Da. Additionally, the antigen-presenting cells
PSG-1 Activate macrophages [55]
branching at the O-6 position occurs in as much as three-fifths of the Glu
through the TLR4 / ROS/
residues in BSP’s backbone, and the terminal sugar residues consist of PI3K/Akt/MAPKs NF-κB
Man residues [39]. Other TCMPs also have specific monosaccharide signaling pathways
composition and MW as listed in Table 1. To conclude, the composition Antitumor activity BCAP-1 Activate macrophages [56]
and content of monosaccharides in different TCMPs exhibit significant through the NF-κB signaling
pathways
variations, consequently determining different biological activities. APS Down-regulation of p65 and [57–59]
p50 expression and NF-κB
2.2. Pharmacological action transcription activity
Mir-675-mediated
inactivation of PI3K/AKT and
Polysaccharides are proved to be one type of the important active
JAK/STAT pathways
components in TCM. In recent years, it has been found that some inhibited SH-SY5Y cells
traditional Chinese medicine polysaccharides can treat some diseases. Upregulation of cc chemokine
Currently reported pharmacological action of TCMPs are expounded as receptor 7 expression
activates dendritic cells (DCs),
follows (Table 2).
cytotoxic T lymphocytes
(CTL), and natural killer (NK)
2.2.1. Immunomodulatory activity cells in mesenteric lymph
An increasing number of studies have confirmed the significant nodes.
immunomodulatory effects of traditional Chinese medicine poly­ LNT Activation of ROS-TXNIP- [60]
NLRP3 inflammasome and
saccharides in recent years. LBP can enhance the phagocytosis ability of
ASK1/p38 MAPK signaling
macrophages and promote the proliferation of dendritic cells, thus pathway
protecting the integrity of intestinal mucosal immune barrier [51–54]. GLP Activation of p38 and JNK- [61,62]
GLP can exert immunomodulatory effects through various pathways MAPK pathways and blocking
[54]. Firstly, it can directly activate multiple immune cell types, of extracellular signal-
regulated kinase /MAPK
including T cells, B cells, NK cells, and neutrophils, and the interaction of signaling pathway
GLP with the dectin-1 receptor, Toll-like receptors, or mannose re­ Specific recognition of dectin-
ceptors (MR) has been documented to induce an immune response. 1, mannose receptor (MR),
Moreover, GLP can bind to CR3 receptors on granulocytes, neutrophils Toll-like receptor (TLR) 4,
complement receptor 3 (CR3),
and NK cells to enhance immune regulation. Furthermore, it has been
scavenger receptor, and TLR2
established in GLP that the chemical composition, conformation and on the surface of effector cells
physical properties of TCMPs can affect their immunomodulatory ac­ ASP Blocked JAK-STAT, BMP- [63]
tivities. For example, the main chain of GLP contains beta-(1→3) bonds SMAD, and ERK pathways
and a varying number of beta-(1→6) branches, which have significant AP Decreased expression of [64]
proliferating cell nuclear
immunomodulatory activity [54]. Last but not least, a new immune antigen
regulator derived from GLP, PSG-1, has been proved to be activated by Antioxidant activity BSP Scavenging free radicals [65]
TLR4/7/PI3K/Akt/MAPKs/NF-κB signaling pathways [55]. (DPPH and ABTS) and
reducing ability
ASP Up-regulation of PPARγ and [66]
2.2.2. Antitumor activity
down-regulation of iNOS,
TCMPs have been confirmed to exhibits anticancer properties that SOD and CAT
are mediated by various mechanisms. Bupleurum polysaccharide Inhibited cell apoptosis and
(BCAP-1) exerts antitumor effects by activating macrophages via NF-κB the expression of
signaling [56]. In the A549 xenotransplantation model, APS can inflammatory cytokines (IL-
1β and TNF-α)
significantly inhibit the proliferation of A549 and NCI-H358 cells, Promoted the expression of
down-regulate the expression of p65, p50 and the transcriptional ac­ anabolic genes (Col2a1,
tivity of NF-κB, therefore inhibit tumor growth [57]. Meanwhile, APS aggrecan, and SOX9)
may inhibit tumorigenesis of SH-SY5Y cells through Mir-675-mediated Decreased expression of
catabolic genes (MMP-1, − 3
inactivation of PI3K/AKT and JAK/STAT pathways [58]. Wang et al.
and − 9)
proved that APS can be used as a mucosal adjuvant to activate dendritic APS Inhibited oxidative stress [67]
cells (DCs), cytotoxic T lymphocytes (CTL) and natural killer cells (NK) Anti-inflammatory LBP reversed up-regulation of [68]
in mesenteric lymph nodes by upregulating the expression of chemokine activity TNF-α, IL-1β, and MCP-1
receptor 7, thus enhancing anticancer activity [59]. Lentinan exerts a mRNA levels
increased TLRs/NF-kB
synergistic apoptosis effect in A549 cells by activating signaling pathway
ROS-TXNIP-NLRP3 inflammasome and ASK1/p38 MAPK signaling
(continued on next page)
pathway [60]. Yang et al. found that GLP can simultaneously activate
the p38 and JNK-MAPK pathways and block the kinase/MAPK signaling

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Table 2 (continued ) that preconditioning with ASP could mitigate legumin A-induced liver
Pharmacological TCMPs The mechanism of action References injury by downregulating pro-inflammatory cytokines, including TNF-α,
activities IFN-γ, IL-2, and IL-6 [70]. In addition, Baicalin has been found to inhibit
ASP Increased GSH level and [69,70]
the NF-κB signaling pathway and the activate the NLRP3 inflammasome.
inhibited hepatocyte It also suppresses the production of pro-inflammatory cytokines (IL-6,
apoptosis IL-1β, and TNF-α), increases TJ protein expression to enhance intestinal
Down-regulated pro- barrier function, thereby improving ulcerative colitis [71]. Ephedra
inflammatory cytokines (TNF-
Stapf polysaccharide (ESP) alleviates lung inflammation through regu­
α, IFN-γ, IL-2 and IL-6)
APS Inhibited NF-κB signaling [71] lation of the TGF-β1/Smad2 pathway [72]. BSP effectively blocks Ang
pathway and NLRP3 II-induced upregulation of NADPH Oxidase 4 (NOX4) and reduces the
inflammasome overexpression of TLR2, thereby exerting anti-inflammatory effects
Inhibited the production of [73]. Moreover, ASP combined with Codonopsis polysaccharide im­
pro-inflammatory cytokines
(IL-6, IL-1β, and TNF-α)
proves colitis in mice by activating colon tissue AhR and regulating in­
ESP-B4 Regulated TGF-β1/Smad2 [72] testinal flora through upregulation of isovaleric acid and butyric acid in
pathway fecal samples [74].
BSP Blocked Ang II-induced [73]
upregulation of NADPH
2.2.5. Others
oxidase 4 (NOX4)
Reduced the overexpression In addition to the aforementioned pharmacological effects, studies
of Toll-like receptor 2 (TLR2) have demonstrated that LBP possesses anti-aging properties, as it can
APS+CGP Activated colon tissue AhR [74] regulate age-related genes (Sirt1, NAMPT, Prx1), inhibit cell cycle ar­
Upregulated isovalerate and rest, enhance antioxidant enzyme activity, and mitigate cell membrane
butyric acid in stool samples
others LBP controlled age-related genes [54]
oxidative damage [54]. Additionally, AAP also exerts an anti-aging ef­
(Sirt1, NAMPT, Prx1) fect on mice by augmenting the activity of GSH-PX and XOD in the liver
Inhibited cell cycle arrest while reducing MAO activity in brain tissue [75]. And also, Yam poly­
AAP Increased activity of GSH-PX [75] saccharide exhibits scavenging capabilities against free radicals and
and XOD in mouse liver
displays anti-aging effects [76].
Reduced MAO activity in the
brain
CYP scavenging free radical [76] 3. Construction strategy of TCMPs in NDDSs

TCMPs are a sort of good building block for NDDSs, with multiple
pathway which is regulated by extracellular signals, resulting in cell active functional groups in their structure and can form polysaccharide
cycle arresting and apoptosis of HL-60 [61]. Additionally, with glucose derivatives with compounds of different structures through esterifica­
and mannose, GLP can be recognized by receptors on cell surfaces, tion, Schiff base reaction, and Maillard reaction [77]. The
including the Dectin-1, the Mannose Receptor (MR), the Toll-like Re­ above-mentioned polysaccharide derivatives are capable of more easily
ceptor 4, the Complement Receptor 3 (CR3), the Scavenger Receptor, building NDDSs [37]. Nowadays, there are some methods have been
and the TLR2 on effector cell surface, thereby reducing the occurrence proposed to prepare TCM polysaccharide-based NDDS. The main strat­
and development of cancer [62]. Recent studies have shown that ASP egy utilized in previous study to construct the NDDS of TCMPs are
can inhibit tumor growth by blocking JAK-STAT, BMP-SMAD and ERK polyelectrolyte complexes, self-assembly, and Layer by layer assembly.
pathways [63]. Glehnialittoralis polysaccharide may decrease the Constructing strategy of specific TCMPs in NDDSs may be dependent on
expression of proliferating cell nuclear antigen, leading to cell cycle its chemical structure and application goal [78] (Fig. 1).
arresting in S phase and G2/M phase. Consequently, it inhibits cell
proliferation and migration and significantly induces apoptosis of cancer 3.1. Polyelectrolyte complexes (PEC)
cells [64].
Polyelectrolytes are biological macromolecules having dotted or
2.2.3. Antioxidant activity charged functional groups [79–82]. PEC, no covalent crosslinking agent
Excessive accumulation of free radicals can lead to severe cellular is required, and can be formed by mixing two polyelectrolytes with
damage. The rough layered structure and α-glucose-ranose configura­ differing charges [83]. Existing research has confirmed that most TCMPs
tion of BSP, coupled with its high clearance capacity (DPPH and ABTS) carry negative charges on the surface, enabling them to spontaneously
and strong reduction ability, enable it to effectively function as an form a variety of stable PEC structures in water through electrostatic
antioxidant [65]. ASP exerts a protective effect on H2O2-induced interaction with polycations compounds [84,85]. For instance, posi­
oxidative stress injury in human chondrocytes by up-regulating PPARγ tively charged chitosan and negatively charged AAP interact electro­
and down-regulating iNOS, SOD, and CAT [66]. Furthermore, Zhuang statically to form stable, nanoscale polyelectrolyte complexes that
et al. showed that ASP inhibits H2O2-induced chondrocyte injury in rats effectively load Dox for the treatment of breast cancer [86]. Another
by suppressing apoptosis and the expression of inflammatory cytokines TCMPs-based PEC nanoparticles were prepared by employing negatively
(IL-1β and TNF-α), promoting the expression of anabolic genes (Col2a1, charged polyelectrolyte tremella fuciformis polysaccharide (TFP) and
aggrecan, and SOX9), while reducing the expression of catabolic genes positively charged CS. The constructed nanostructures demonstrated
(MMP-1, − 3, and − 9) [66]. It is noteworthy that APS can inhibit notable temperature sensitivity across 10–60˚C and can be used as car­
oxidative stress pathways to reduce liver damage [67]. riers for encapsulating other nutrients or drugs to improving oral ab­
sorption efficiency [87] (Fig. 2).
2.2.4. Anti-inflammatory activity
TCMPs have also been confirmed to possess good anti-inflammatory 3.2. Self-assembly
effects. LBP show promise in improving CCL4-induced liver fibrosis by
reversing the upregulation of TNF-α, IL-1β, and MCP-1 mRNA levels, A self-assembled structure is formed by joining the basic building
along with reducing the heightened expression of TLRs/NF-kB signaling blocks of a material spontaneously [88]. TCMPs have the structural basis
pathways [68]. ASP significantly reduces liver injury by increasing GSH of forming NPs through self-assembly technology. They are
levels and inhibiting hepatocyte apoptosis [69]. Wang et al. discovered aqueous-soluble and may be hydrophobically modified by chemically or

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J. Wang et al. Biomedicine & Pharmacotherapy 173 (2024) 116330

Fig. 1. The scheme for the construction strategy of TCM polysaccharides in NDDSs.

Fig. 2. Preparation process diagram of Dox/AAP-CS-NPs and TFP/CS NPs.

physically to generate amphiphilic polysaccharide derivatives [89,90], 3.2.2. Self-assembly of polysaccharide-drug graft polymer
such as polysaccharide-hydrophobic compounds, polysaccharide-drug In 1975, Ringsdorf proposed the use of polysaccharide-drug conju­
graft polymers, polysaccharide-protein polymers etc, capable of gates as a means to deliver hydrophobic agents [20]. These conjugates
self-assembling into NPs with various nanostructures [91]. consist of three key components: a water-soluble system, the medication
itself, and a biodegradable spacer that connects the two. In current
3.2.1. Self-assembly of polysaccharide-hydrophobic compounds literature, TCMPs-drug conjugates are primarily synthesized via Schiff
TCMPs possess the ability to form amphiphilic polymer derivatives base reactions, followed by self-assembly into nanoparticles in suitable
when combined with hydrophobic compounds such as deoxycholic acid, media. An example of this is the self-assembly of LBP-DOX nanoparticles
stearic acid, alpha-tocopherol succinate, and histidine [92]. In aqueous [94]. In an aqueous system, these nanoparticles exhibit a spherical shape
systems, these derivatives can self-assemble into micelles. The esterifi­ with a diameter of approximately 200 nm. They possess high pH
cation reaction is the primary method employed for the preparation of sensitivity, physical stability, and the ability to release the medication
amphiphilic polymer derivatives, taking advantage of the abundant continuously within tumor cells, thereby exerting anti-tumor effects.
hydroxyl groups present in TCMPs structures. For instance, histidine Similarly, DOX-conjugated LNT nanoparticles have been reported to
(His) was used to hydrophobically modify AAP polymers (His-AAP) enhance the anti-tumor efficacy of DOX while reducing its systemic
through esterification reactions, resulting in the formation of nano­ adverse effects. The grafting rate of LNT-DOX conjugates was deter­
micelles with desirable size, uniform morphology, and high encapsula­ mined to be 6.5±0.65 mg per 100 mg of DOX. Importantly, the
tion efficiency [93]. Similarly, self-assembled nanoparticles (NPs) self-assembled LNT-DOX nanoparticles demonstrated elevated
composed of hydrophobically modified BSPs were investigated by anti-cancer capabilities in breast cancer cells while reducing cytotoxicity
chemically attaching stearic acid (SA) to BSP chains for the transport of in human normal cells [95].
docetaxel (DTX). These micelles exhibited an average particle size of
96.27 ± 1.21 nm. Moreover, DTX-SA-BSPs copolymer micelles demon­ 3.2.3. Self-assembly of polysaccharide-protein conjugate
strated the ability to overcome the efflux effect of P-glycoprotein (P-GP) TCMPs can interact with protein via the Maillard reaction generating
pumps, leading to enhanced anti-cancer efficacy compared to docetaxel a polysaccharide-protein conjugate, and the conjugate can prone to self-
injection [35]. assemble into polysaccharide-stabilized protein NPs with heat treatment

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[50]. Because of the potent steric repulsion of polysaccharides, NPs hyaluronic acid encapsulated copper-apiate complex [101]. Chen et al.
obtained by Maillard conjugates in this system display exceptional sta­ designed an injectable self-healing hydrogel of chitosan and Konjac
bility at high temperatures, pH, and ionic strength [96,97]. glucomannan through Schiff base reaction, which can better promote
Polysaccharide-stabilized protein NPs (CP3) were readily formed using wound healing [102]. Yang et al. has prepared bletilla polysaccharide
homologous proteins and TCMPs from RP to produce conjugates with a (OBSP)-chitosan (CS) composite hydrogel (OBSP-CS-LP hydrogel using a
certain degree of glycation via dry heating. The CP3 NPs about simple method [103]. In a 3D printing study, Yan et al. prepared a snake
125.5 nm, spherical. More importangly, TCMPs greatly increased pro­ melon/ASP hydrogel [104].
tein NPs stability [50].
4. Types of NDDSs fabricated using TCMPs
3.2.4. Layer by layer self-assembly
The Layer by layer (LbL) assembly, driven by electrostatic adsorp­ Miscellaneous NDDSs with varied compositions and nanostructures,
tion, relies on the interaction between the positive charge of polycation such as polymeric micelles, dendritic polymers, liposomes or vesicles,
electrolyte and the negative charge of polyanion electrolyte. Previous inorganic particles, and prodrug assembly, have been devised and con­
research has indicated that natural polyelectrolyte substances are structed to meet the unique administration requirements. Currently,
favored for LbL assembly because of their innate compatibility with reported TCMPs-based NDDSs mainly comprise nanoparticles, nano­
living organisms and ability to break down naturally. Lentinan, a emulsions together with nanomicelles which are described as follows
polysaccharide derived from botanical sources, demonstrates remark­ and summarized in Table 3.
able compatibility and antibacterial properties, as well as antitumor
activity. Moreover, the LbL assemble method was utilized to create bio- 4.1. Nanoparticles
friendly polyelectrolyte multilayers using poly-L-ornithine (PLO) and
carboxymethyl lentinan (LC), and these layers were applied to coat the Nanoparticles hold significant potential for enhancing treatment
mesoporous silica nanoparticles (MSNs) surface. Li et al. synthesized efficacy through various mechanisms, including improved solubility of
nanoparticles, denoted as 4-aminophenyl β-glucagon-galactoside (Gal- hydrophobic drugs, prolonged blood circulation time, targeted drug
NH2)/mulligan leaf polysaccharide-lysozyme/luteolin (Gal-MPL/Lut), delivery, and controlled release within specific tissues or cells. In recent
using an amide reaction, a self-assembly process, and electrostatic in­ years, there has been considerable interest in the development of
teractions [98]. Additionally, the biosafety and biocompatibility of TCMPs-based nanoparticles for intelligent drug delivery. For example,
mesoporous silica nanoparticles (MSNs) were further enhanced through Se-TCMPs nanoparticles (NPs) have been designed to address the
surface modification with carboxymethyl lentinan using a LbL assembly. adverse effects of selenium deficiency on overall health, including the
In summary, the amalgamation of natural polymers and LbL assembly development of chronic diseases like atherosclerosis, hypoimmunity,
technology holds immense promise as a drug delivery carrier, presenting and cancer. To tackle this issue, Meng et al. employed a chelation
an advantageous platform for disease treatment [99]. method using sodium selenite to prepare highly enriched APS NPs (Se-
APS NPs), which effectively supplement selenium deficiency in the
3.2.5. Self-assembly of hydrogel human body [107]. In another study by Cai et al., nanoscale selenium
TCMPs are an important class of polymers that can be used to was ingeniously combined with laminarin polysaccharides (LP) as a
construct nano-hydrogel. Studies have found that TCMPs can form modifier, demonstrating remarkable cytotoxicity and
hydrogels by cross-linking with other substances. These hydrogels apoptosis-inducing activity against HepG2 cells [117]. Moreover,
exhibit excellent water retention, biocompatibility, and biodegrad­ TCMPs serve a dual role as reducing agents and stabilizers during the
ability, making them widely utilized in the medical industry to encap­ synthesis of silver nanoparticles, offering advantages such as avoiding
sulate NDDSs [2]. As an illustration, Chen et al. presented a dual potential toxic side effects associated with other materials used in silver
dynamic cross-linked hydrogel utilizing oxidized bletilla poly­ nanoparticle synthesis and enhancing their antibacterial properties
saccharide. This hydrogel, in combination with gallic acid grafted chi­ [118].
tosan, can be formed through two dynamic cross-linking methods
involving Schiff base and pyrogallol Fe3+ [100]. Additionally, an in situ,
ASP based hydrogel has been constructed to load polymer micelle of

Table 3
Construction strategy and application of TCMPs based NDDSs.
Polysaccharide types Construction strategy NDDS forms Loaded agents Roles in NDDSs References

LBP Polysaccharide–drug conjugate Nanoparticles Doxorubicin Drug delivery carrier [94]

/ Nanoparticles pTGF-β1 Gene delivery carrier [105]
APS Self-assembly Nano micelle Curcumin Auxiliary anti-tumor, drug delivery carrier, [106]
/ Nanoparticles / Reactant, stabilizer [107,108]
ASP Self-assembly Nano micelle Doxorubicin Targeted carrier, [25]
Self-assembly Nano micelle Curcumin Targeted carrier, [26,109]
Self-assembly Nanoparticles Curcumin Targeted carrier [27]
Self-assembly Nanoparticles Curcumin drug delivery carrier [18]
GLP Self-assembly Nanoparticles 10-hydroxycamptothecin Drug delivery carrier [110]
/ Nanoparticles Bismuth sulfide Auxiliary anti-cancer [111]
BSP Self-assembly Nano micelle Docetaxel, Medicine carrier [112]
Nano micelle Doxorubicin [113,114]
Nano micelle curcumin [115]
AAP Polyelectrolyte complexes Nanoparticles Doxorubicin Medicine carrier [86]
Self-assembly Nano micelle Docetaxel [93]
LNT Polysaccharide–drug conjugate Nanoparticles Doxorubicin Medicine carrier Auxiliary anti-tumor [95]
Self-assembly Nanoparticles Ursolic acid [116]
LP / Nanoparticles / Modifier, stabilizer [117]
GP / Nanoparticles / Reactant, stabilizer [118]
RPP Self-assembly Nanoparticles Doxorubicin Drug delivery carrier [50]

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4.2. Nanoemulsions (PEI)-modified yam polysaccharide (CYP)-coated PLGA nanoparticles

(CYP PEI). CYPP-PEI may produce a Th1/Th2 mixed and Th1-biased
Nanoemulsion is a metastable thermodynamically colloidal disper­ immune response, meaning it would produce a robust and long-lasting
sion that exhibits transparent or translucent states [119,120]. Research immune response [132]. As a result, there is hope that these nano­
shows that the size of the droplets can be decreased by using TCMPs as particles will lead to the development of more potent anticancer
emulsifiers to improve the solubilization and stability of hydrophilic or medications.
hydrophobic ingredients [121]. Therefore, Hohenbuehelia serotina Extensive research on nanocarrier materials has revealed that func­
polysaccharides based nanoemulsions have been constructed to address tional carrier materials, such as ligands and stimuli-responsive compo­
the low solubility and unstable issues, displaying outstanding nents, can better fulfill the body’s requirements, particularly natural
sustained-release properties in the simulated stomach fluid [122]. compounds with biological activity, such as TCMPs. Ganoderma luci­
Alzorqi et al. extracted β-D-glucan polysaccharides from Ganoderma dum polysaccharide (GLP), a bioactive component of Ganoderma luci­
lucidum and incorporated them into palm olein-based nanoemulsions, dum, possesses various merits including anti-cancer activity,
generated higher antioxidant activity compared to free β-D-glucan immunomodulation, and antioxidant properties. GLP has been utilized
[123]. for the delivery of the chemotherapeutic agent 10-hydroxy camptothe­
cin in a redox and pH-dual responsive smart drug delivery system
4.3. Nanomicelles (RCGDDH NPs). In this system, GLP serves as the hydrophilic group
linked with rutin and dihydroartemisinin (DHA). Notably, GLP, acting as
Nanomicelles are generated by the self-aggregation of amphiphilic a carrier, exhibits inherent anti-cancer activity and can enhance the anti-
copolymers in an aqueous system, with a stable core-shell structure cancer efficacy [110]. Liu et al. designed a copolymer of BSP based on
[124]. TCMPs are reported as prominent hydrophilic segments that can dual pH and REDOX responses, which self-assembled into micelles (the
be grafted onto hydrophobic polymers, and hydrophobically modified docetaxel-loaded BSP-SS-SA micelles) in an aqueous environment and
polysaccharide polymers can spontaneously form micelles in water so­ embedded docetaxel in them. The BSP-SS-SA micelles loaded with
lution [125]. For instance, the hydrophobic drug curcumin (Cur) was docetaxel considerably increased the release of anticancer medications
effectively encapsulated into polymer micelles AAAF@Cur, a at the tumor site and improved the therapeutic impact when compared
hypoxia-responsive and ASP-based liver-targeting amphiphilic polymer to docetaxel solution [96]. Lichun Zhao et al. developed a pH-sensitive
micelles AA/ASP-AZO-Fc (AAAF), exhibiting high biocompatibility, BSP micelle system for targeted delivery of docetaxel (DTX). Enhanced
hypoxic response to drug release, increased cell uptake, effectively cellular uptake of the micelles, as well as enhanced tumor targeting and
improved proliferation inhibitory efficacy, and a liver-specific targeting anticancer efficacy was observed，as compared with DTX injection
function [109]. Also, there are some BSP-based micelles such as [133]. However, these systems often face challenges related to their
BSP-ss-SA loaded DTX micelles with intelligent response-controlled capture by the reticuloendothelial system (RES). Therefore, further
release characteristics [112] and functionalized BSP micelle etc pro­ exploration and incorporation of alternative materials capable of
posed [113]. These TCMPs-based micelles offer considerable promise in evading RES engulfment are necessary to address the issues associated
hydrophobic drug delivery. with nanoparticle-based treatments. To tackle the aforementioned issue,
Fang and colleagues developed innovative ASP-based nanoparticles
5. Roles of TCMPs in NDDSs (ASP-PBA/GACDB@Cur) with the tumor microenvironment (TME) -
responsive charge-reversal and mitochondrial targeting capabilities
5.1. Delivery carriers (Fig. 3). In this study, cationic chitosan (CS) derivatives were employed
as the nanoparticle core, while the surface modification with negatively
5.1.1. Drug delivery charged AS-PBA prevented RES clearance. The results revealed that
The limited solubility and severe toxic side effects of chemothera­ these core-shell nanoparticles effectively delivered the medication to the
peutic drugs hinder their clinical applications and anti-tumor efficacy tumor site without being cleared by RES, leading to significantly pro­
[126–128]. To overcome the drawbacks of conventional approaches, longed drug retention within tumor tissues [18].
TCM-based NDDSs have been explored as potential solutions for cancer Currently, various TCMPs have been explored as carriers with re­
treatment. TCMPs offer remarkable advantages [120] and can serve as ceptor targeting functions [12]. Specifically, Astragalus polysaccharides
skeleton materials for the development of NDDSs, enabling the targeted (ASPs) serve as an excellent example. They are highly prevalent and
delivery of medicines. As an example, APS have been explored as a novel
carrier for delivering curcumin (Cur) to enhance its anti-tumor effects.
Wang et al. successfully synthesized dual-targeted nanocarriers,
quercetin-3 ’3-dithio-dipropionic acid-APS-folic acid (QDAF), where
ASP play an immunomodulatory role [106]. Additionally, a mixed
micelle system based on Bletilla polysaccharide (BSP) (DOX@FA-BS­
P-SA/TPGS) exhibited superior safety, blood compatibility, and
enhanced anti-tumor efficacy compared to free doxorubicin (DOX) and
single micelles of DOX@FA-BSP-SA [114]. In a recent study, Zhang et al.
investigated the potential of Folate-mediated stearic acid modified
Bletilla striata polysaccharide (FA-BSP-SA) for targeted delivery of DOX
to tumor tissues. It demonstrates a significantly enhancement on the Dox
uptake of tumor cells and consequently inhibit the proliferation and
migration of tumor cells [129]. Chen et al. revealed that nanoparticles
containing BSP effectively inhibited the proliferation of human gastric
cancer cell line MKN45. This is likely due to the abundance of hydro­
philic hydroxyl groups in BSP, which can improve cell targeting by
introducing cholesterol units [130]. And also, BSPs-SA nanoparticles
showed a more substantial inhibitory effect on the proliferation of 4T1
cells compared to Dopapfi-® nanoparticles [131]. Wusiman et al. have Fig. 3. Illustration of self-assembled ASP nanoparticles escaping phagocytosis
created a vaccine delivery method using polyethylenimine in the reticuloendothelial system.

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J. Wang et al. Biomedicine & Pharmacotherapy 173 (2024) 116330

exhibit strong affinity for the asialoglycoprotein receptor (ASGPR), production of cytokines and recruitment of immunosuppressive cells
which is overexpressed on the surface of hepatocellular carcinoma cells. [151].
Therefore, ASPs are ideal for designing active targeting NDDSs to Recent pharmacological research has demonstrated that traditional
enhance drug accumulation at tumor sites and improve therapeutic ef­ Chinese medicine (TCM) polysaccharides can alleviate the immuno­
ficacy. Notable examples include DOX/ASP-DOCA NPs [25], Cur/ACNPs suppressive state of the TME by activating immune cells, stimulating
[27], and GACS-Cur @ RBCm NPs [26]. Moreover, macrophage cytokine production, and reversing TME immune evasion, thereby
mannose receptors (MRs) and β-glucan receptors have the ability to exerting anti-tumor effects [152]. Inspired by their immunomodulatory
recognize Bletilla polysaccharides (BSP). Thus, BSP carriers can be and anti-neoplastic properties, TCMPs have gained significant attention
effectively utilized for targeted delivery to macrophages [134,135]. For in the field of cancer nanomedicine. TCMPs-based NDDSs efficiently
instance, 4-(hydroxymethyl) pinacol phenyl borate (PBAP), a reactive transport anti-cancer medications to the tumor site while modulating
oxygen species (ROS)-responsive group, was incorporated into BSP to the TME and facilitating tumor immunotherapy. Correlative studies
create an amphiphilic ROS-sensitive BSP (oxi-BSP) carrier structure for have shown the potential of an enzyme-responsive NDDS (ASP-PP-DOX)
curcumin (CUR) delivery. In this system, BSP selectively targets the for targeted tumor therapy. In this system, ASPs act as effectors to
receptors on the surface of (KC) [115]. ASP exhibits a high affinity for enhance the TME and promote immune function, while also serving as
binding to Asialoglycoprotein receptor (ASGPR), the most widely carriers for precise drug delivery to the tumor tissue. The synergistic
recognized target receptor in hepatocytes. Wang et al. synthesized anti-tumor effect is achieved through the combined action of chemo­
amphiphilic cholesterol succinate ASP conjugates through esterification therapeutic drugs and ASPs, which can be rapidly released in the pres­
and created spherical self-assembled nanoparticles (ACNPs) and loaded ence of matrix metalloproteinase 2. Mechanistically, ASP production
them with CUR. These ACNPs, through ASGP-mediated uptake, may modulate the Th1/Th2 balance in the TME, increase interleukin-2
demonstrated efficient accumulation in hepatocytes. This suggests that (IL-2) secretion, reduce IL-10 secretion, and work in conjunction with
they hold promise as drug carriers for delivering medications to the the chemotherapeutic drug DOX to exert an anti-tumor effect [153].
liver, where they can exert their protective effects [27]. Zhang et al. The TME poses significant challenges for effective immunotherapy
modified ASP by adding a hydrophobic group (deoxycholic acid), which due to its immunogenic and immunosuppressive nature [154]. Although
was then utilized to coat DOX to create ASP-DOCA NPs. The ASP-DOCA certain chemotherapy drugs, such as etoposide and oxaliplatin, can
NPs exhibit selective targeting of HepG2 tumors through ASGPR, facil­ induce immunogenic cell death (ICD) and have systemic toxicity against
itating increased accumulation of DOX in tumors and demonstrating cancer cells [155,156], their resulting immunogenicity is often insuffi­
heightened anti-tumor efficacy [25]. cient to effectively prevent tumor growth, relapse, and malignant
transformation [157]. The use of TCMPs, such as LNT, as tumor adju­
5.1.2. Gene delivery vants has been found to enhance ICD and stimulate robust immune re­
Gene therapy offers widespread potential applications in the treat­ sponses [158]. Inspired by the drug supplementary approach in TCM,
ment of hemophilia [136], cystic fibrosis [137], cancer [138], and brain Mao et al. [116] developed a self-assembling nanodrug called LNT-UA
diseases [139]. Accurate transfer of nucleic acids to the cell nucleus and for colorectal cancer immunotherapy, using the natural bioactive com­
their efficient expression inside the cell are prerequisites for successful ponents ursolic acid (UA) and LNT without additional vectors. In this
gene therapy [140,141]. The absence of efficient and secure gene vec­ formulation, LNT functions as a biocompatible excipient to increase UA
tors, however, is impeding the development of gene therapy [142,143]. solubility and bioavailability while UA causes ICD. Furthermore, LNT
TCMPs are toxic-free, nonimmunogenic, and flexible enough to be functions as a multipurpose immunopotentiator, inducing maturation of
altered to meet particular requirements [144–146], thus cationic TCMPs dendritic cells (DC) and repolarizing tumor-associated macrophages
may emerge as the most promising options for non-viral gene carriers (TAMs) from an antitumorigenic M1 phenotype to a protumorigenic M2
[106]. To carry plasmid DNA encoding for transforming growth one. LNT-UA effectively enhanced the TME that suppresses the immune
factor-beta 1 (TGF-β1), for example, three novel non-viral gene vectors system, triggered both non-specific and specific immunity, and slowed
known as cationized LBP (cLBP) NPs were developed. Outstanding cell the growth of the tumor in a CT-26 colorectal cancer tumor model. GLP
vitality in transfected cells revealed negligible cytotoxicity of cLBP. It functions as an adjuvant and demonstrates anti-cancer characteristics by
turned out that cLBP may be a promising gene delivery vehicle [105]. inhibiting the TME’s production of FoxP3, lowering IL-10 and TGF-β
Deng et al. proposed a novel approach by introducing a branched pol­ secretion, lowering the number of regulatory T cells (Tregs) recruited
yethyleneimine modified ASP nanoparticle as a safe and effective into tumor tissues, eliminating the immunosuppressive effects of Treg
non-viral gene vector. The cationized ASP (cASP) was capable of form­ cells, and tipping the immunological scales in favor of effector T cells
ing spherical nano-scaled particles (cASP-pTGF-β1NP) when coupled [159,160]. The researchers developed GLP-conjugated bismuth sulfide
with the plasmid encoding TGF-β1. This nanoparticle was employed for nanoparticles (GLP-BiNPs) with immunological activity based on these
transfecting human umbilical cord mesenchymal stem cells and rat bone properties [111]. The bismuth element in GLP-Bi NPs absorbs X-rays to
marrow mesenchymal stem cells. The findings suggest that cASP holds induce tumor cell destruction, while GLP reshapes TME immune func­
potential as a novel non-viral gene vector, providing valuable insights tion and inhibits tumor growth by inducing tumor cell apoptosis.
for the application of TCMPs in gene therapy. Moreover, compared to Bi NPs alone, GLP-Bi NPs exhibited altered
distribution patterns with rapid accumulation at tumor sites. Conse­
5.2. Auxiliary antineoplastic quently, GLP-Bi NPs may contribute to enhanced DC maturation,
increased activity and quantity of CD8+T lymphocytes in cancer tissue,
Cancer, characterized by uncontrolled proliferation, invasiveness, and elevated IFN-γ levels. Furthermore, GLP conjugation appears to
metastasis and recurrence, has become a leading cause of morbidity and protect the kidney from inadvertent damage caused by Bi NPs [111]
mortality worldwide [147,148]. Current standard treatments, including (Fig. 4).
surgery, chemotherapy, and radiation, have limitations in completely The auxiliary anti-tumor effect of TCMPs and their ability to prevent
eradicating malignancies. Chemotherapy remains an essential thera­ clearance of nanomedicines by the RES, enance the accumulation of
peutic option for cancer patients [149]. However, its effectiveness is nanomedicines at tumor sites, and play a crucial role in overcoming
compromised by non-selectivity and the complex TME, leading to sys­ multidrug resistance in cancer treatment. As reported, insufficient drug
temic toxicity [150]. The TME plays a critical role in tumor develop­ penetration into tumor tissues and inadequate intracellular drug release
ment, metastasis, immune evasion, and drug resistance [150]. The TME are two significant factors contributing to multidrug resistance [161].
contributes to treatment intolerance and unfavorable prognosis by For the purpose of tackling this issue, an nano-targeted delivery system
establishing an immunosuppressive environment through the known as Quercetin-3′3-dithiodipropionic acid-astragalus

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Fig. 4. Diagram of the assisted anti-tumor mechanism of the traditional Chinese medicine polysaccharide nanodrug delivery systems.

polysaccharides-folic acid (QDAF) was effectively produced and their efficacy and therefore hampers their potential for development.
self-assembled. This approach effectively inhibits the development of Consequently, enhancing the solubility of poorly water-soluble medi­
multidrug resistance in estrogen receptor-positive breast tumors. Addi­ cations has become a prominent focus of research in the field of phar­
tionally, APS was selected as a novel excipient to support Cur’s anti­ macy. Previous studies have revealed that increasing the concentration
cancer activities because of its established immunoregulatory properties of polysaccharides in water extracts enhances the extraction rate of
[106]. Furthermore, because of the small size, nanoparticles used in various water-insoluble active compounds, suggesting a potential role of
nanomedicine can be readily captured by the reticuloendothelial system polysaccharides in solubilization. Building upon this knowledge, Zhao
(RES), resulting in decreased drug accumulation. APS were then et al. introduced a novel acidic branched polysaccharide, vinegar-baked
developed to tackle this limitation and resolve the associated issue Radix Bupleurum polysaccharides-3 (VBCP-3), derived from VBCP, to
[106]. Significantly, Combination therapy stands out as a promising investigate the solubilization effects of polysaccharides. In an aqueous
treatment option for cancer, offering the potential to overcome multi­ solution, VBCP-3 forms micelles that encapsulate the insoluble compo­
drug resistance. nents through the interplay of hydrogen bonds and hydrophobic forces.
VBCP-3 exhibits non-toxicity and demonstrates a significantly higher
solubilization effect on baicalin and rhein compared to Tween 80 at
5.3. Other
equivalent concentrations [170]. In terms of the underlying mecha­
nisms, thermodynamic experiments have shown the crucial involvement
5.3.1. Reducing agent and stabilizer
of Van der Waals forces and hydrogen bonds in the interaction between
Silver nanoparticles (AgNPs) have long been acknowledged for their
drugs and polysaccharides [171].
potent antimicrobial activity against a wide range of microorganisms
[162,163]. Their antibacterial capability has garnered significant
6. Challenges and prospects of TCMPs in NDDSs
attention [108]. The successful synthesis of AgNPs relies heavily on the
choice of reducing agents. Natural polysaccharides have emerged as
TCMPs play a significant role in the field of NDDSs due to their
promising candidates for both reduction and stabilization during AgNPs
ability to integrate medicines and excipients. They offer several ad­
synthesis [164–167]. For instance, Sridhar et al. developed an effective
vantages over synthetic polymers, including easy modification and the
method utilizing a semi-synthetic carboxymethyl tamarind poly­
ability to generate diverse nanodrugs [20]. These polysaccharides
saccharide for in situ reduction and capping in AgNPs synthesis [168].
exhibit favorable biological properties and activities, such as targeted
However, studies investigating the use of TCMPs in AgNPs production
delivery of drugs to specific cells or tissues [121], co-loading of multiple
are scarce [108]. Thus, Ma et al. proposed the potential utilization of
drugs to combat multidrug resistance in cancers and enhance thera­
functional TCMPs for the synthesis of antibacterial AgNPs. They suc­
peutic efficacy [172], thereby enhancing their utility in nanomedicine
cessfully synthesized AgNPs using Astragalus membranaceus poly­
[35]. Consequently, TCMPs and their derivatives have emerged as prime
saccharide (AMWP) as a reducing agent and stabilizer. The resulting
candidates for sustainable nanotechnology applications [94].
AMWP-AgNPs exhibited uniform spherical morphology, approximately
However, the clinical translation of TCMPs-based NDDSs remain
60 nm in size, and excellent dispersibility. Moreover, AMWP-AgNPs
challenging due to their natural product nature. The key challenge lies in
demonstrated remarkable antibacterial effects against clinically iso­
the extraction, purification, and yield enhancement processes, as there is
lated multidrug-resistant bacteria and reference strains at relatively low
currently no standardized quality control system for these procedures
concentrations. Additionally, Glycyrrhiza polysaccharide (GP) may
[173]. Additionally, the complex structure and wide range of molecular
stabilize silver nanoparticles [118]. GP served as both the reducing
weights pose difficulties in understanding the structure-function rela­
agent and stabilizing agent in this process. These GP-stabilized silver
tionship of TCMPs, hindering their design and clinical application in
nanoparticles showed promising antibacterial properties, highlighting
nanomedicine. The distribution process, action pathway, and mecha­
their potential as novel antibacterial biomaterials [118].
nism of TCMPs as anti-tumor adjuvants remain unclear, and their spe­
cific impact on immune function is not well understood. Therefore,
5.3.2. Solubilizer
comprehensive exploration and the development of scalable production
A significant proportion, exceeding 40%, of newly discovered drug
and quality control methodologies are necessary for the clinical appli­
candidates in the modern pharmaceutical industry suffer from poor
cation of TCMPs-based NDDSs.
water solubility [169]. This solubility issue is a critical determinant of

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