Herbal polysaccharides—a rising star in engineering multifunctional biomaterials for tissue repair and regeneration

Abstract

Herbal polysaccharides (HPs) derived from traditional Chinese medicine are rapidly emerging as versatile biomaterials in the field of tissue regeneration. These natural glycans function as unique carrier-effector systems that harmonize inherent biocompatibility with profound pharmacological activities. This review systematically surveys recent advances in the immunomodulatory, antioxidant, antitumor and gut microbial-regulating activities of HPs. We emphasize that these pharmacological activities are largely dictated by intricate structure–activity relationships, in which parameters such as molecular weight, glycosidic linkages and branching patterns serve as key determinants. Building on these structural insights, we further explore how strategic chemical modifications, including sulfation, carboxymethylation and selenization, can precisely tailor the bioactive properties of polysaccharides to enhance therapeutic efficacy. Special emphasis is placed on advanced biomaterial systems, ranging from bio-instructive hydrogels and micro-/nanoparticles to microneedles, and on their applications in accelerating tissue regeneration. This review also addresses current challenges related to structural heterogeneity and clinical translation. Looking forward, artificial intelligence and machine learning offer powerful tools to decode the glycan code, enabling predictive SAR modeling and rational design of HP-based biomaterials. These approaches, combined with 3D bioprinting, may transform HPs into precision-engineered platforms for spatially and temporally controlled therapies. Future efforts should also focus on elucidating how HPs interact with subcellular organelles and tracking their in vivo metabolic fate, as these insights are essential for closing the gap between natural complexity and clinical standardization.

Graphical Abstract

Graphical Abstract.

Introduction

Polysaccharides are one of the four basic substances in living organisms and are commonly found in plants, animals and microorganisms. They consist of long carbohydrate chains linked by α- or β-glycosidic bonds, which grant them unique physical and chemical properties [1]. Owing to their matrix-forming properties and biocompatibility, natural polysaccharides, such as chitosan, alginate and hyaluronic acid, are extensively employed in tissue regeneration [2, 3].

Beyond these predominantly structural roles, a distinct class of polysaccharides derived from traditional Chinese medicine (TCM), herbal polysaccharides (HPs), has emerged as a unique category of biomaterials. Unlike inert scaffolds that merely provide mechanical support, HPs serve dual roles as structural matrices and bioactive effectors. By integrating structural and therapeutic functions (such as immunomodulatory, antioxidant, antitumor, or gut microbiota-regulating effects) within a single macromolecular entity, HPs offer capabilities that extend beyond those of conventional synthetic or purified natural polymers, making them well suited for multifunctional biomaterial engineering [4–8].

However, their direct biomedical applicability may be limited by the inherent structural instability of natural HPs under varying conditions of pH, temperature and oxidative stress [9]. Notably, the abundance of reactive functional groups on their molecular chains, such as hydroxyl, amino and carboxyl, counterbalances this limitation by providing a versatile platform for chemical modification or grafting of bioactive ligands. These modifications enable the development of polysaccharide derivatives with properties tailored for specific regenerative needs. The pharmacological activities of HPs are determined by their molecular features, including molecular weight (MW), monosaccharide composition, glycosidic linkage patterns, branching density and spatial conformation [10]. Deciphering these structure–activity relationships (SAR) therefore provides the basis for rational chemical modification. Identifying the structural motifs that govern specific bioactivities makes it possible to introduce functional groups, such as sulfate, carboxymethyl or selenium moieties, that remodel polysaccharide chains, alter conformational behavior and enhance therapeutic efficacy in a predictable manner. This structure-driven strategy converts inherently variable natural extracts into precisely tailored biofunctional materials.

The application of HPs in advanced biomaterial systems further illustrates their functional versatility. HP-based nanoparticles can improve drug targeting and serve as effective agents to enhance therapeutic outcomes [11, 12], while HPs can also promote drug absorption by modulating microbial metabolism via paracellular or transcellular pathways, thereby increasing drug bioavailability [13]. Notably, when HPs serve as both drug delivery matrices and therapeutic agents, a synergistic effect is more likely to occur [10, 14]. Beyond the above functions, HPs contribute to the fabrication and performance of hydrogels by modulating mechanical strength, rigidity and degradation kinetics, which are critical for regulating tissue repair and regeneration processes [15].

This review integrates the pharmacological activities, SAR, chemical modification strategies and biomaterial formulation of HPs, with an emphasis on how these aspects collectively enable the development of HP-based material systems, such as hydrogels, micro-/nanoparticles and microneedles (MNs), for tissue repair and regeneration. This review first summarizes the core pharmacological mechanisms of native HPs that contribute to a pro-regenerative microenvironment, establishing the therapeutic rationale for their application in tissue repair. It then examines how macromolecular features govern bioactivity, laying the groundwork for structure-guided chemical modifications. Building on this, we discuss how targeted chemical modifications can overcome the inherent limitations of natural polysaccharides while enhancing the functions needed for specific tissue regeneration contexts. Finally, we review the translation of modified HPs into advanced biomaterial systems, highlighting how system design and intrinsic bioactivity work together to guide the regeneration process. By tracing the path from structural determinants through chemical engineering to ultimate biomedical application, this review identifies key translational bottlenecks and outlines design principles for developing HP-based biomaterials in regenerative medicine.

Pharmacological activities of HPs

As principal bioactive constituents of TCM, HPs exhibit multiple pharmacological activities, such as immunomodulation [5, 16], anti-inflammation [17], antioxidant [18], gut microbiota modulation [19] and antitumor effects [20] (Table 1, Figure 1). Among the many effects of HPs, immunomodulation and antioxidant activities are the most important and unique. Unlike small-molecule drugs that possess only bioactivity, HPs combine pharmacological functions with the physicochemical properties of natural polymers, enabling their direct use as structural scaffolds and delivery matrices. Furthermore, while most small-molecule drugs act on a single molecular target, the compositional and structural diversity of HPs enables them to engage multiple receptors and activate diverse signaling cascades on immune cells, collectively driving a wide range of biological effects. These pharmacological actions collectively contribute to shaping a pro-regenerative microenvironment.

Table 1.

HPs as multifunctional therapeutic agents: a summary of bioactivities and applications.

Polysaccharide name	Source	Bioactivity	Experimental model/evidence	Key molecular mechanism	Main biological outcomes	Application
Ginseng polysaccharides (GP)	Panax ginseng C. A. Meyer	1, 2, 3	Tumor immunotherapy; myocardial injury models	Activates TLR4/MyD88/NF-κB signaling; modulates kynurenine/tryptophan ratio	Potentiated anti-PD-1/PD-L1 efficacy; protection of cardiomyocytes via mitochondrial regulation	Antitumor [4]; immunotherapy [5]; anti-ulcerative colitis [13]; cardiomyocyte protection [97, 180]
Red Ginseng polysaccharides (RGP)	Panax ginseng C.A. Meyer	3, 4, 5	Myocardial injury; Alzheimer’s models	Induces ferroptosis via AQP3 inhibition and PI3K/Akt pathway suppression	Reduced lipid peroxidation; enhanced neuronal survival in AD models	Cardiomyocyte protection [97, 180]; Alzheimer’s disease [181]; antitumor [91, 182]
American Ginseng polysaccharides (AGP)	Panax quinquefolius L.	1, 2	Ulcerative colitis; cardiac models	Inhibits MAPK/NF-κB signaling; upregulates gut-derived short-chain fatty acids (SCFA)	↓ Pro-inflammatory cytokines; reduced neutrophil recruitment; intestinal barrier protection	Cardiomyocyte protection [97]; anti-ulcerative colitis [17]; antitumor [183]
Astragalus polysaccharides (APS)	Astragalus membranaceus	1, 2, 6, 7	Wound healing; diabetic cardiomyopathy; vascular models	Activates Nrf2/HO-1 and TLR4 pathways; suppresses BMP10 signaling	↓ MDA by >40%; ↑ IL-12 and TNF-α; ↓ diabetic cardiac hypertrophy	Antitumor [19, 87]; wound healing [38, 45]; anti-ulcerative colitis [184]; diabetic cardiomyopathy [98]; vascular dysfunction [185]
Angelica sinensis polysaccharides (ASP)	Angelica sinensis	1, 4, 7	Liver regeneration; osteoarthritis models	Regulates PPARγ/SOD2/ROS pathway; activates JAK2/STAT3/HK2-mediated glycolysis	Enhanced glycolysis; accelerated liver tissue regeneration; ↓ cartilage degradation	Osteoarthritis [186]; drug carrier [7]; antitumor [187]; mastitis [188]
Bletilla striata polysaccharides (BSP)	Bletilla striata	6, 7, 8, 9	Diabetic infected wounds; skin repair	Upregulates VEGF expression; provides physical scaffolding via dynamic crosslinking	Accelerated re-epithelialization; promoted fibroblast and endothelial cell proliferation	Wound healing [14, 161]; targeted drug delivery [20]
Lycium barbarum polysaccharides (LBP)	Lycium barbarum	2, 4, 10	Primary Sjögren’s syndrome; tumor cell lines	Suppresses SLC7A11/GPX4 axis; downregulates Tfh/Th17 cell populations	↑ Treg/Tfh and Treg/Th17 ratio; ↓ Glandular inflammation; induction of ferroptosis	Antitumor [93]; Sjögren’s syndrome [34]; influenza [99]
Ganoderma lucidum polysaccharides (GLP)	Ganoderma lucidum	5, 6	Diabetic wound healing; neuroinflammation	Inhibits TLR4/NF-κB; stimulates Wnt/β-catenin and TGF-β1 protein secretion	↑ CD206 (M2 marker) by ∼4-fold; ↓ Wound closure time by 30–50%	Neuroinflammation [36]
Ginkgo biloba polysaccharides (GBLP)	Ginkgo biloba	5, 6	Alopecia; depression models	Modulates VEGF and HGF expression; reshapes gut microbiota composition	Promoted hair follicle growth; stimulated secretion of trophic factors	Antidepression [189]; hair-growth promotion [37]
Dendrobium officinale polysaccharides (DOP)	Dendrobium officinale	1, 2	Intestinal barrier; depression models	Activates LPL-mediated IL-22 secretion; stimulates Lgr5+ intestinal stem cells	Enhanced mucosal immunity; improved depressive-like behaviors	Immunotherapy [190]; antidepression [101]
Radix Puerariae lobatae polysaccharides (PLP)	Radix Puerariae lobatae	1, 7	Hyperlipidemia; alcoholic liver disease	Activates farnesoid X receptor pathway; modulates bile acid metabolism	Modulated bile acid metabolism; improved lipid profile	Hyperlipidemia [191]; alcoholic liver disease [192]
Polygonatum sibiricum polysaccharides (PSP)	Polygonatum sibiricum	7, 11	Sarcopenia models; in vitro antioxidant	Activates PI3K/Akt/mTOR signaling; scavenges DPPH and hydroxyl radicals	Reduced muscle atrophy; potent antioxidant capacity (comparable to vitamin C)	arcopenia [193]; General antioxidant [194]
Achyranthes bidentata polysaccharides (ABP)	Achyranthes bidentata	1, 2, 12	Rheumatoid arthritis; nephropathy	Inhibits ROS/NF-κB signaling; suppresses MMP-9/MMP-13 expression	↓ Joint inflammation; reduced extracellular matrix degradation; Hypoglycemic effects	Rheumatoid arthritis [12]; diabetic nephropathy [195]; hypoglycemic [196]
Ginger polysaccharides (GP)	Zingiberis Rhizoma Recens	1, 2	Immunosuppressed mice; tumor models	Enriches beneficial Muribaculaceae/Lactobacillaceae; induces MDSC apoptosis	↑ Lactobacillus (15–25%); ↓ Rikenellaceae (60–75%); Restored SCFA	Intestinal barrier protection [57]; antitumor [197]
Hirsutella sinensis polysaccharides (HSP)	Hirsutella sinensis	1	High-fat diet murine models	Upregulates thermogenesis markers; enriches gut Parabacteroides goldsteinii	Nearly 50% weight reduction; elimination of systemic inflammation	Antitumor [198]; anti-obesity [66]
Sparassis latifolia polysaccharides (SLP)	Sparassis latifolia	2, 7, 13	Renal injury; diabetic lipid metabolism	Regulates lipid metabolism; suppresses oxidative stress-mediated autophagy	Protection against lead-exposed kidney injury; synergistic hypoglycemic effects	Antitumor [199]; renal injury [200]; drug carrier [201]
Pine pollen polysaccharides (PPP)	Pine pollen	14	Ulcerative colitis; wound healing	Activates JAK2-STAT3 signaling pathway; regulates Th17/Treg homeostasis	Improved intestinal barrier; accelerated wound closure in mice	Wound healing [15]; anti-ulcerative colitis [202]
Chinese yam polysaccharides (CYP)	Dioscorea opposita Thunb.	1, 2, 7	Vaccine adjuvant; colitis models	Downregulates pro-inflammatory cytokines; upregulates antioxidant enzyme activities	Potent humoral and cellular immune response enhancement; ↓ inflammation	Anti-ulcerative colitis [203]; general antioxidant [46]; vaccine adjuvant [204]
Citri Reticulatae Pericarpium polysaccharides (CRPP)	Citrus reticulata Blanco	1	Obesity models	Modulates fatty acid metabolism pathway; reshaping gut microbiota profiles	↓ Body weight gain; improved metabolic homeostasis in HFD-fed mice	Anti-obesity [65]
Polygonatum cyrtonema Hua polysaccharides (PCP)	Polygonatum cyrtonema Hua	1, 6, 7	Post-traumatic stress disorder; ulcerative colitis models	Suppresses synaptic injury and neuroinflammation; enhances SCFA production	Improved memory and behavior in post-traumatic stress disorder models; enhanced intestinal integrity	Anti-ulcerative colitis [205]; neuroprotection [52]

1. Gut microbiota regulation. 2. Immunomodulation. 3. Mitochondrial regulation. 4. Ferroptosis induction. 5. Neuroprotection. 6. Anti-inflammatory. 7. Antioxidant. 8. Hemostasis. 9. Microenvironment regulation. 10. Antiviral. 11. Anti-aging. 12. Prebiotic. 13. Drug delivery. 14. Promotes cell proliferation.

↑: Up regulate; ↓: down regulate.

DPPH: 2,2-diphenyl-1-picrylhydrazyl; PPARγ: peroxisome proliferator-activated receptor gamma.

Figure 1.

Pharmacological mechanisms of HPs. HPs orchestrate tissue homeostasis and regeneration through four synergistic axes. Immunomodulation: HPs modulate the TLRs/NF-κB [27] and MAPK [17] pathways, promoting macrophage polarization from the pro-inflammatory M1 phenotype to the pro-healing M2 phenotype. This shift stimulates the release of trophic factors, including IL-10, TGF-β, VEGF and HGF [37]. Antioxidant activity: Activation of the Keap1-Nrf2/ARE [48, 49] signaling axis upregulates antioxidant enzymes such as SOD and GSH-Px, thus effectively scavenging ROS and reducing MDA levels to mitigate oxidative cellular damage. Antitumor effects: HPs induce tumor cell apoptosis and ferroptosis by suppressing the PI3K/Akt/mTOR and Slc7a11/GPX4 axes, while concurrently bolstering NK cell cytotoxicity and tumoricidal cytokine secretion [91, 93]. Gut modulation: Acting as prebiotics, HPs reshape the gut microbiota (e.g. enriching Lactobacillus), thereby enhancing short-chain fatty acids (SCFA) production to fortify the intestinal barrier and maintain systemic immune homeostasis.

Immunomodulatory and anti-inflammatory effects as therapeutic hubs

Appropriate inflammation facilitates the clearance of pathogens and necrotic debris, thereby supporting the formation of a regenerative microenvironment, whereas persistent inflammation causes further tissue damage and delays the repair process [21]. A successful regenerative outcome, therefore, depends on the timely resolution of inflammation and the transition from a pro-inflammatory to a pro-healing microenvironment [22]. HPs promote this transition by interacting with pattern recognition receptors (PRRs) on immune cells, most notably toll-like receptor (TLR), dectin-1 and the mannose receptor (MR) [23].

TLR4 has been identified as a central mediator through which HPs act via multivalent interactions that differ from the canonical recognition of lipopolysaccharide, leading to receptor clustering, endocytosis and downstream signaling that drives macrophage phenotypic activation [24]. Systematic studies on Astragalus membranaceus polysaccharides (APS) reveal their ability to stimulate the expression of interleukin (IL)-12 and tumor necrosis factor (TNF)-α via the TLR4/MyD88/NF-κB pathway, contributing to early-stage wound cleansing [25, 26]. Conversely, a neutral polysaccharide from American ginseng (AGP-A) suppresses the production of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and reduces neutrophil infiltration by inhibiting the MAPK signaling pathway [17]. Another notable example is the Ganoderma lucidum polysaccharide (GLP), which promotes M2 macrophage polarization and anti-inflammatory cytokines (IL-10 and TGF-β) expression by suppressing the TLR4/NF-κB pathway, while activating the TGF-β1/Wnt/β-catenin signaling axis to stimulate fibroblast proliferation and thereby accelerate diabetic wound healing [27]. These examples illustrate the diverse and sometimes opposing immunomodulatory effects of HPs depending on their structural features and the pathological context. Notably, even the same polysaccharide can display dual effects according to the activation state of the target cells. These dual regulative effects have been demonstrated with Panax quinquefolius polysaccharides, which were found to stimulate NO and TNF-α production in resting macrophages while suppressing the release of these mediators in lipopolysaccharide-activated cells [28]. This regulatory flexibility helps explain why HPs can function across diverse pathological settings, from chronic wounds to autoimmune conditions, and makes them particularly suited to the dynamic demands of tissue regeneration.

Beyond TLR4, HPs also engage other PRRs that contribute to the overall immunomodulatory response. MR, a C-type lectin that recognizes mannose, fucose and N-acetylglucosamine residues, mediates the endocytosis of mannose-rich polysaccharides and can attenuate inflammatory signaling [29]. For instance, GLPs have been shown to activate MR, leading to increased IL-10 production and suppressed secretion of pro-inflammatory cytokines [30]. Dectin-1, the principal receptor for β-(1→3)-glucans with β-(1→6)-side chains, activates signaling through the Syk/CARD9 cascade, leading to NF-κB activation and the production of cytokines such as TNF-α and IL-1β [31]. Recent studies have further demonstrated that polysaccharide-induced Dectin-1 signaling promotes dendritic cell maturation and enhances antigen presentation, thereby linking innate immune activation with downstream adaptive responses [32]. HPs can also modulate the NOD-like receptor protein 3 (NLRP3) inflammasome, a cytosolic multiprotein complex that controls the maturation and secretion of IL-1β and IL-18. HPs, such as Dictyophora indusiata polysaccharide, have been found to facilitate the priming step of NLRP3 activation by upregulating TLR4 expression and promoting NF-κB p65 nuclear translocation, although they do not trigger the second, assembly step of the inflammasome [33]. Conversely, other HPs like APS, have been reported to inhibit NLRP3 inflammasome activation under conditions of excessive inflammation, contributing to the resolution of tissue damage. The structural basis for this bidirectionality has been partially elucidated for APS, where the TLR4/MyD88 axis serves as the core signaling module, while MR and NLRP3 function as co-regulatory inputs that fine-tune the output [23].

Above from innate immunity, HPs also shape adaptive immune responses within the wound microenvironment. Lycium barbarum polysaccharides (LBP) have been shown to mitigate salivary gland inflammation in primary Sjögren’s syndrome by reducing the populations of effector follicular helper T (Tfh) and Th17 cells, while concurrently upregulating the Treg/Tfh and Treg/Th17 cell ratios [34]. These immunomodulatory effects are not limited to local tissue repair. Dendrobium officinale polysaccharides, for instance, have been reported to restore cyclophosphamide-induced immunosuppression by increasing immune organ indices and immunoglobulin levels and by promoting the proliferation of splenic lymphocytes [35]. Beyond direct immunomodulation, emerging evidence suggests that HPs can regulate the expression of growth factors, pointing to a broader spectrum of biological effects [36]. For instance, water-soluble polysaccharides from Ginkgo biloba leaves were found to promote hair growth by modulating vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and inflammation-related signaling pathways [37]. Collectively, these findings underscore the central role of HPs in modulating immune responses and alleviating inflammation, highlighting their therapeutic potential in tissue repair and regeneration.

Antioxidant activity of HPs

Excessive oxidative stress impedes tissue regeneration by causing irreversible damage to cell membranes, proteins and DNA, ultimately compromising cellular function and regenerative capacity. HPs function as antioxidants through two complementary routes: direct free radical scavenging and the activation of endogenous antioxidant defense systems [38, 39]. Liu et al. reported that a polysaccharide extracted from Rehmannia Radix Praeparata exhibited an ABTS⁺ radical scavenging rate of 91.3% [40]. Similarly, polysaccharides from Sagittaria sagittifolia showed a dose-dependent ABTS⁺ scavenging activity (86.11%), while their hydroxyl radical (•OH) scavenging rates peaked at 99.56% [41]. These potent scavenging activities are primarily attributed to the structural characteristics of HPs, specifically their abundant hydroxyl and carboxyl groups, which serve as hydrogen or electron donors to stabilize reactive species, alongside glycosidic bonds that facilitate the neutralization of free radicals [41, 42]. Beyond these inherent chemical properties, the interplay between MW and monosaccharide composition further modulates their direct antioxidant efficacy [43, 44]. By directly alleviating oxidative damage, these polysaccharides safeguard cell membrane integrity and metabolic homeostasis, thereby preserving cellular viability and creating a favorable microenvironment for tissue regeneration [45].

In addition to their direct scavenging capabilities, HPs can also enhance cellular resilience against environmental stressors through regulating the activity of the endogenous antioxidant defense system [46, 47]. This modulation is primarily achieved by activating the Nrf2-Keap1 signaling pathway, a sophisticated thiol-based sensor-effector apparatus essential for maintaining redox homeostasis [48, 49]. Under physiological conditions, Nrf2 is sequestered in the cytoplasm by Keap1 and targeted for proteasomal degradation [50]; however, HPs such as APS and GLP promote the dissociation of Nrf2 from the Keap1 complex, allowing Nrf2 to translocate into the nucleus and bind to antioxidant response elements, triggering the transcription of a comprehensive cytoprotective suite [48]. This downstream response includes the induction of phase II detoxifying enzymes, such as heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1, alongside a robust battery of antioxidant enzymes including superoxide dismutase, catalase and glutathione peroxidase [48]. The resulting activation effectively mitigates oxidative damage, evidenced by a marked reduction in malondialdehyde levels [49]. Different from the transient effect of direct scavenging, this Nrf2-mediated enzyme induction provides sustained antioxidant protection that meets the prolonged oxidative demands encountered in chronic tissue repair settings, such as diabetic wound healing, diabetic bone defect repair and neurotrauma recovery [45, 51, 52].

Except for disrupting cellular redox balance, ROS impairs the efficacy of therapeutic agents by degrading proteins, inactivating bioactive molecules, or inducing apoptosis of transplanted cells, thereby hindering the effective accumulation and utilization of therapeutics at the lesion site [53]. Consequently, direct radical scavenging by HPs is particularly critical during the early inflammatory phase of tissue repair, whereas Nrf2-mediated antioxidant enzyme induction sustains cellular defense throughout prolonged tissue remodeling. The temporal separation of these antioxidant mechanisms enables HPs to simultaneously provide immediate and sustained protection via direct scavenging and Nrf2 activation across multiple tissue types. Yet this approach faces critical challenges stemming from structural inconsistency in natural polysaccharides. Variations in MW distribution, uronic acid content and branching density between batches substantially alter the contribution of each antioxidant mechanism [54]. Therefore, developing standardized extraction and fractionation protocols, combined with targeted chemical modifications that predictably modulate the balance between direct scavenging and Nrf2 activation, is essential for incorporating HPs into a reliable, controllable design feature of clinical-grade regenerative biomaterials with defined antioxidant performance.

Microbiota modulation

Systemic regulation via the gut-target organ axis

The gut microbiota is recognized as a systemic regulator of tissue repair, with its compositional and functional integrity influencing regenerative outcomes across multiple organ systems, including skin, bone and liver [8, 55, 56]. HPs function as prebiotics that selectively promote the growth of beneficial bacteria while inhibiting pathogenic species [57, 58]. For instance, ginger polysaccharides were found to enrich beneficial bacteria like Muribaculaceae and Lactobacillaceae with relative abundance increases of 15–25% while suppressing harmful Rikenellaceae by 60–75%, thereby restoring SCFA (short‑chain fatty acids) levels and strengthening intestinal barrier function in immunosuppressed mice [57].

The capacity of HPs to remodel the gut microbiota is governed by their structural features, since the MW, monosaccharide composition and glycosidic linkage patterns of a given polysaccharide determine which bacterial taxa can access and metabolize it [59]. Fermentation of HPs by the gut microbiota generates SCFA, primarily acetate, propionate and butyrate, which serve as signaling molecules that engage G proteincoupled-receptors receptors (GPR41, GPR43 and GPR109A) on intestinal epithelial cells and immune cells [60]. Activation of these receptors on dendritic cells and macrophages promotes a tolerogenic phenotype characterized by increased IL-10 secretion and reduced pro-inflammatory cytokine production [61]. Butyrate also functions as a histone deacetylase inhibitor in naive CD4⁺ T cells, inducing histone H3 acetylation at the Foxp3 locus and driving the differentiation of regulatory T cells [62]. The resulting expansion of the Treg pool reinforces systemic immune homeostasis, establishing an anti-inflammatory environment that supports tissue regeneration at distant sites.

The impaired angiogenesis, cellular dysfunction and elevated oxidative stress that characterize metabolic diseases collectively delay tissue repair and predispose individuals to chronic wounds [63]. A key driver of these pathological features is gut microbiota dysbiosis, which reduces SCFA production, compromises intestinal barrier function and elevates systemic inflammation [64]. HPs have been shown to counteract these effects. By restoring gastrointestinal barrier integrity and reshaping gut microbiota composition, HPs can attenuate high-fat diet-induced weight gain, hyperglycemia and dysregulated fatty acid metabolism [65], while enriching specific beneficial taxa such as Parabacteroides goldsteinii, which was identified as the predominant mediator of the anti-obesity effects [66].

In excess of their local effects on the gut, HPs can influence tissue repair at extra-intestinal sites through the gut-organ axis. SCFA released into the circulation have been shown to act on the bone marrow, where they influence hematopoietic stem cell differentiation and bias macrophage precursors toward an anti-inflammatory phenotype [67], and on the liver, where butyrate enhances hepatocyte proliferation partly through AMPK activation [68]. In a murine model of chronic kidney disease, a polysaccharide-based hydrogel designed for colon-targeted release increased serum propionate and butyrate levels, activated PPARγ signaling and attenuated renal fibrosis [69], demonstrating that appropriately formulated HPs can achieve therapeutic effects at distant organs without requiring direct local application.

Local microbiota modulation at barrier tissues

In addition to their systemic effects mediated by the gut microbiota, HPs can also modulate microbial communities at extra-intestinal barrier sites, most notably the skin [70]. Whether similar direct modulation occurs at other barrier tissues, such as the oral cavity and the uterine endometrium, remains an open question that warrants future investigation. Here, we focus on the skin as the best‑characterized example, while briefly considering how the principles established may extend to other barrier sites.

These local microbial ecosystems share a common organizational principle in which resident commensals maintain barrier integrity and immune homeostasis through the constitutive production of antimicrobial peptides and the competitive exclusion of pathogens [70, 71]. Upon injury or disease, this equilibrium is disrupted, allowing pathogenic species to overgrow and sustain chronic inflammation that delays tissue repair.

Commensals such as Cutibacterium spp., Corynebacterium spp. and Staphylococcus epidermidis are the dominant microbiota on healthy skin and contribute to host defense through multiple mechanisms [70]. Staphylococcus epidermidis, for instance, can regulate γδT cells and induce perforin-2 expression, which in turn promotes the intracellular destruction of Staphylococcus aureus [71]. Following injury, this microbial community undergoes a marked shift, characterized by a decline in commensal populations and an overgrowth of pathogenic species, most notably S. aureus and Pseudomonas aeruginosa [72, 73]. These pathogens form biofilms that shield them from host immune clearance and antibiotics [74], while secreting virulence factors that degrade extracellular matrix (ECM) components and sustain a chronic inflammatory state [72]. Biofilm formation is particularly prevalent in diabetic wounds and is recognized as a major contributor to delayed healing. S. aureus and P. aeruginosa are consistently identified as the dominant isolates in diabetic foot infections, with biofilm-producing strains accounting for over 70% of clinical cases [75, 76]. This dysbiosis disrupts the coordinated signaling between the host immune system and the local microbiome, thereby delaying the transition from inflammation to proliferation and preventing wound closure.

HPs can counter such dysbiosis through mechanisms similar to those observed in the gut. Their negatively charged functional groups, such as sulfate, carboxyl and phosphate moieties, interact electrostatically with the positively charged components of bacterial cell walls and membranes. This electrostatic adsorption can increase membrane permeability, disrupt membrane integrity and ultimately inhibit pathogen proliferation [77, 78]. Polysaccharide fractions derived from Trametes versicolor, Pleurotus ostreatus and Hericium erinaceus have been reported to inhibit the growth of S. aureus (including MRSA strains), P. aeruginosa, Escherichia coli and Candida albicans by 30–70% at a concentration of 20 mg/mL, suppressing biofilm formation commonly [79]. A polysaccharide isolated from Zizania latifolia was further shown to promote macrophage migration and enhance the phagocytosis of S. aureus without inducing cytotoxicity, suggesting that HPs can facilitate pathogen removal both by physical disruption of bacterial structures and by activating innate immune effector functions [80]. Alongside these antimicrobial effects, HPs can selectively support the growth of beneficial skin commensals through prebiotic effects, while simultaneously promoting M2 macrophage polarization and regulatory T-cell recruitment [81]. Collectively, these multi-pharmacological activities create a microenvironment that favors wound repair over chronic inflammation. In a murine model of S. aureus-infected diabetic wounds, a Gastrodia elata polysaccharide-based triple-network hydrogel was found to accelerate wound closure and reduce bacterial colonization, demonstrating that appropriately designed HP-based materials can simultaneously address the microbial and immunological components of wound healing [82].

Collectively, HPs establish a tissue regeneration-supportive systemic environment through microbiota remodeling and metabolite production, reducing pathological inflammation and metabolic dysfunction while enhancing intestinal barrier integrity. These prebiotic and metabolic effects represent indirect but essential mechanisms that complement the direct immunomodulatory and antioxidant activities in promoting tissue repair and regeneration. However, several challenges remain before these findings can be translated into clinical practice. Natural polysaccharides vary in structure from batch to batch, leading to inconsistent fermentation profiles and SCFA production [83], which makes it difficult to predict how a given preparation will behave in vivo. Inter‑individual differences in baseline microbiota composition further compound this variability, as the metabolic fate of a polysaccharide depends on the enzyme repertoire of the resident microbial community [84]. Moreover, while direct effects of HPs on the skin microbiome are increasingly supported by experimental data, evidence for similar direct modulation at other barrier tissues (e.g. oral cavity, uterine endometrium) remains indirect. The causal chain linking HP administration to local microbial remodeling at these sites has yet to be established. Future work should address these gaps using metagenomic or metatranscriptomic methods to analyze local microbiota after HPs treatment [85, 86]. Unlike 16S rRNA sequencing, which accurately captures microbial diversity well but often underestimates or misinterprets functional capabilities [86], metatranscriptomics directly reveals which bacterial taxa are actively metabolizing a given polysaccharide and which carbohydrate-active enzymes are induced [86]. In addition, researchers should develop biomaterial systems that deliver HPs directly to specific barrier tissues. These efforts will help determine whether the principles established in the skin apply to other barrier sites and ultimately enable better use of HP-microbiome interactions in regenerative medicine.

Antitumor activity and other pharmacological activities

Antitumor activity

Tumor remains a multifaceted global health challenge. Accumulating evidence demonstrates that HPs exert notable antitumor effects through direct cytotoxicity against tumor cells, immune system enhancement and synergism with conventional chemotherapeutic agents [4, 8, 87]. Polysaccharides derived from A. membranaceus and G. lucidum trigger macrophage M1 polarization and dendritic cell maturation via TLR4/NF-κB and MAPK signaling pathways, leading to increased secretion of tumoricidal cytokines such as TNF-α, IFN-γ and IL-12, which subsequently activate CD8⁺ T lymphocytes for tumor clearance [87, 88]. Polysaccharide from Panax notoginseng residue also engages TLR receptors to form TLRs–MyD88 complexes, activating NK cell cytotoxicity and pro-inflammatory cytokine secretion [89, 90]. Direct suppression of tumor growth involves the PI3K/Akt/mTOR axis, as seen with Lentinan, which promotes apoptosis via caspase-3 activation and Bcl-2 downregulation [91, 92]. In addition, certain HPs, including those from L. barbarum and red ginseng, induce ferroptosis by suppressing the SLC7A11/GPX4 pathway, thereby overcoming apoptosis resistance [91, 93–95]. Besides, by inhibiting VEGF-mediated pro-angiogenic signaling, HPs concurrently restrict tumor nutrient supply, demonstrating a multi-targeted approach that integrates immune-driven and cell-autonomous antitumor activities [96].

The immunomodulatory pathways activated by HPs, such as TLR4, Dectin-1 and MR signaling, are shared by both antitumor immunity and tissue repair [23, 87, 88]. This overlap suggests a conceptual possibility that HPs might be used in clinical situations that demand both tumor suppression and tissue regeneration. Examples include skin defects after skin tumor removal, as well as bone defects caused by breast cancer bone metastasis, where a material that can both inhibit tumor growth and promote tissue regeneration would be highly beneficial. However, direct experimental evidence supporting this dual application remains limited. Most studies on HP-mediated antitumor activity have been conducted in isolation, without evaluating their effects on subsequent tissue repair processes. Furthermore, the direction of immune modulation required for effective tumor clearance (e.g. sustained M1 polarization) may conflict with that needed for optimal regeneration (e.g. timely transition to M2 phenotype). Therefore, rather than claiming that antitumor mechanisms directly drive regeneration, we emphasize that the bidirectional immunomodulatory capacity of HPs warrants further investigation in clinically relevant models that combine tumor ablation with tissue regeneration. Future studies should systematically evaluate whether HPs can simultaneously suppress residual tumor cells and promote tissue repair and identify structural or formulation parameters that favor one function over the other.

Other pharmacological activities

Beyond the pharmacological activities discussed above, HPs also exhibit a range of additional pharmacological effects. For instance, Panax polysaccharides have been shown to protect cardiomyocytes from injury by regulating mitochondrial biogenesis and function [97]. Another study revealed that APS attenuated diabetic cardiac hypertrophy by suppressing the BMP10 signaling pathway [98]. In addition, the antiviral activity has been observed in certain HPs, either through immunomodulation or direct interference with viral replication [99, 100]. Moreover, owing to the multifaceted pharmacological activities, HPs have emerged as promising candidates for the development of antidepressant drugs [52, 101–103].

SAR of HPs

The diverse pharmacological activities of HPs are intrinsically linked to their complex structures [104]. Understanding the SAR is crucial for harnessing its therapeutic potential in tissue regeneration. By dissecting how primary sequences and higher-order conformations dictate biological outcomes, we can establish a blueprint for designing restorative biomaterials.

MW defines the bioactivity window

As a complex biomacromolecule, the MW of HPs profoundly influences their solubility, viscosity, membrane transport capabilities and higher-order structure formation [105]. This, in turn, directly impacts their diverse biological activities, including antioxidant, immunomodulatory, antitumor, lipid-lowering and antiviral effects. Moderately high-MW polysaccharides (>100 kDa) often possess complex triple-helix conformations that facilitate receptor clustering and potent immune activation, whereas excessively high MW may hinder solubility and tissue penetration [105, 106]. Conversely, low-MW fragments may lose the necessary spatial conformation to bind receptors. Studies on APS have identified an optimal window of 30–50 kDa for maximum immunomodulatory potency [107].

This nonlinear relationship between MW and bioactivity has been systematically validated through the fractionation of crude APS into distinct MW ranges. Comparative analysis of a high-MW fraction (APS-I, >2000 kDa), a medium-MW fraction (APS-II, ∼10 kDa) and a low-MW fraction (APS-III, ∼300 Da) revealed a parabolic relationship, with APS-II identified as the most immunomodulatory fraction [23, 108]. In immunosuppressed mouse models, APS-II was the most effective in restoring immune organ indices, promoting splenic lymphocyte proliferation, inducing Th1-type cytokines (IL-2, IFN-γ) and enhancing NK cell cytotoxicity and IgG secretion [109]. The superior potency of the ∼10 kDa fraction was attributed to its optimal aqueous solubility and low viscosity, which facilitate systemic absorption and efficient engagement with immune cells. In contrast, APS-I showed weaker activity due to poor solubility and high viscosity, while APS-III exhibited minimal activity, indicating that a minimal chain length and specific 3D architecture are prerequisites for immune receptor activation [108].

Monosaccharide composition and glycosidic linkages as primary activity determinants

The monosaccharide composition and molar ratio of HPs serve as the primary structure indicators that determine their physicochemical properties and biological activities. The proportion of monosaccharides directly influences the receptor recognition, solubility and charge characteristics of the polysaccharides. High molar ratios of galacturonic acid (GalA) and arabinose (Ara) are positively correlated with superior antioxidant and anti-inflammatory activities [107, 110]. For instance, in Rubus idaeus L. polysaccharides, the GalA content is directly proportional to their ability to quench free radicals, whereas a high ratio of galactose (Gal) may reduce antioxidant capacity but enhance prebiotic effects by acting as a fermentation substrate for Bifidobacterium [111]. Quantitative evidence further demonstrates that the content of mannose, glucose, xylose and fucose positively correlates with macrophage nitric oxide release, providing direct evidence that monosaccharide profiles are pivotal determinants of HP immunopotency [112].

Branching architecture and higher-order conformation

Although the composition, proportion and MW of monosaccharides influence polysaccharide bioactivity, highly branched HPs typically demonstrate enhanced immunostimulatory and antitumor activities [26, 113]. The rhamnogalacturonan (RG) domain, in particular, is widely recognized as a core functional unit responsible for the immunomodulatory and anti-inflammatory effects of numerous HPs. The branching density within the RG-I domain correlates directly with its binding affinity for key immune receptors such as TLR4 [114]. The AG-II structure can specifically bind to and inhibit galectin-3, thereby exerting antitumor metastasis and anti-inflammatory effects [115]. These highly branched architectures offer abundant binding sites for immune cells, thereby triggering markedly more efficient signal transduction compared to simpler linear chains [116].

Using raspberry pulp polysaccharides as a model, Lu and colleagues developed an artificial neural network (ANN) to predict immune-enhancing activity from structural features, achieving mean absolute percentage errors of 0.21% on the training set and 0.98% on the testing set. By applying Gradient-weighted Class Activation Mapping (Grad-CAM) for explainability analysis, they further identified the principal structural determinants of immunomodulatory activity. These included MW; the content of Ara, Gal and GalA; and, most notably, the specific glycosyl linkage patterns of →3)-Arap-(1→, Araf-(1→, and →4)-Galp-(1→) [113]. All three linkage types are hallmark features of the RG-I domain, providing cross-species, data-driven validation for the central role of RG-I architecture in immune activation discussed earlier. Rather than relying on qualitative empirical correlation, this ANN-Grad-CAM strategy enables quantitative attribution of bioactivity to specific structural motifs. As such, it represents a meaningful step from descriptive SAR toward a mechanism-informed decoding of polysaccharides’ SAR.

A key structural motif consistently identified in bioactive APS fractions is a glucan backbone consisting of α-(1→4)-linked D-glucose residues, decorated with branch chains predominantly at the C6 position [117]. The introduction of such branching enhances structural complexity, which is thought to modulate bioactivity by altering solubility, 3D conformation and the capacity for multivalent attachments to cell surface PRRs.

A particularly instructive contrast emerges when comparing APS with the well-defined fungal β-glucan, lentinan. The latter derives its potent immunomodulatory activity from a highly ordered triple-helical conformation formed by a β-(1→3)-glucan backbone with β-(1→6) branches, enabling high-affinity, specific binding to Dectin-1 [118, 119]. In contrast, APS, with its heterogeneous mixture of α- and β-glycosidic configurations, lacks a singular, structurally defined motif. Yet, this very complexity constitutes a unique advantage: the diverse structural motifs in APS can interact with a broader repertoire of immune receptors, including TLR2, TLR4 and the MR, thereby enabling a “multi-pronged” mode of action that orchestrates a more comprehensive and balanced immunomodulatory outcome [23]. This principle reframes structural heterogeneity as a multi‑target advantage, providing a key to understanding the therapeutic potential of many complex HPs.

Receptor-level validation: from structural parameters to binding specificity

At the receptor level, advanced biophysical techniques have begun to quantitatively link specific structural features to recognition outcomes. In a representative study, surface plasmon resonance and molecular docking were used to systematically compare the binding and activation of Dectin-1, TLR4 and TLR2 by β-glucans from five edible fungi with distinct branching ratios [120]. The results showed a graded immunostimulatory response dependent on branching frequency: β-glucans with branching ratios of 1:3 and 1:4 exhibited markedly stronger receptor binding and downstream activity. Molecular docking further demonstrated that these specific repeating units could adopt energetically favorable conformations by either inserting into or wrapping around receptor monomers or dimers, thereby forming extensive hydrogen bond networks [120]. Together, these findings provide molecular insights into how branching patterns influence receptor selectivity and activation potency. Figure 2 summarizes the three key SAR determinants discussed above. Together, these structural features determine the solubility, receptor binding affinity and overall bioactivity of HPs, providing a rational basis for the chemical modification strategies described in the following section.

Figure 2 Key SAR determinants of HPs. This schematic summarizes three major structural parameters that govern HP bioactivity. MW defines the bioactivity window, with moderate MW offering optimal solubility and viscosity (marked by a star). Monosaccharide composition and glycosidic linkages serve as primary activity determinants, directly influencing receptor recognition. Branching architecture and higher-order conformation trigger more efficient signal transduction by providing multivalent binding sites for immune receptors.

Advanced structural characterization methods for HP conformation analysis

Establishing reliable SAR for HPs requires not only knowledge of their primary structures but also accurate determination of their higher-order conformations in solution. A range of analytical techniques have been applied to this end. For triple-helix polysaccharides, commonly used methods include light scattering, X‑ray diffraction, atomic force microscopy (AFM) and scanning electron microscopy. Among these, the Congo red assay has gained popularity due to its operational simplicity [2]. However, its accuracy remains debated, and over-reliance on this method may lead to ambiguous interpretations of triple‑helix formation.

More refined biophysical techniques now enable atomic‑level characterization of HP conformations. Advanced platforms such as high‑performance size‑exclusion chromatography coupled with multi‑angle laser light scattering provide precise MW distribution and conformational parameters of polysaccharide chains in solution [5, 105]. Meanwhile, 2D nuclear magnetic resonance spectroscopy, including ¹H‑¹H COSY, TOCSY and HSQC, together with methylation analysis, has been widely employed to determine glycosidic linkage patterns and branching architectures [7, 117, 120]. For instance, the structure of a bioactive fraction from APS was systematically elucidated using monosaccharide composition analysis, methylation analysis and NMR spectroscopy, revealing a glucan backbone with α-(1→4)-linked D‑glucose residues and branches at the C‑6 position [120].

For higher‑order conformational analysis, AFM has been successfully applied to directly visualize the spatial arrangement of polysaccharide chains, while circular dichroism (CD) spectroscopy provides complementary information on helical conformations in solution [2, 5]. Together, these multi‑scale analytical strategies, ranging from primary linkage assignment via methylation‑GC‑MS to solution conformation monitoring by AFM and CD, offer a powerful toolkit for dissecting HP SAR and guiding the rational design of HP‑based materials.

Understanding the SAR provides the theoretical basis for the rational chemical modification of HPs, which will be discussed in the next section. However, it must be acknowledged that a complete understanding of HP SAR remains challenging, as obtaining homogeneous polysaccharide samples with precisely defined structures for comprehensive sequential and 3D analysis continues to be a major obstacle [23]. Overcoming this challenge will require continued integration of advanced spectroscopic and computational tools. Still, the SAR principles established so far already offer valuable guidance for designing targeted modifications to optimize the immunomodulatory, antioxidant and pro‑regenerative properties of HPs.

Strategic structural tailoring and mechanisms of HPs

Although numerous natural HPs exhibit a range of pharmacological activities, their inherent limitations, such as poor dimensional stability, low thermoplasticity and excessive hydrophilicity, may restrict their biomedical applications to some extent. Since the biological activity of HPs is intimately related to their chemical structures, strategic chemical modification offers a favorable approach to overcome these limitations and tailor polysaccharide properties for specific applications [121–124]. Mechanistically, these modifications enhance bioactivity not merely by adding functional groups but by fundamentally remodeling the macromolecular chain conformation, MW distribution and solvent accessibility (Figure 3). Current research primarily focuses on several key modification categories such as targeted substitution, precision scission for MW optimization and biofunctional conjugation.

Figure 3.

The effect of chemical modifications on the SAR of HPs. This figure shows how chemical modification transforms native HPs into derivatives with enhanced biological activity. On the left, a native HPs chain folds into a compact coil, with its bioactive domains buried inside. After the introduction of functional groups such as sulfate, phosphate, carboxymethyl, or selenium, the chain extends into a more open conformation. This structural change exposes previously hidden regions, such as RG-I clusters, while also improving water solubility or increasing amphiphilicity. These structural adjustments allow the modified polysaccharide to interact more effectively with immune receptors like TLR4 or Dectin-1, and may also penetrate cell membranes more easily. The diagram links functional groups introduction to conformational changes and ultimately stronger bioactivity, providing a clear basis for designing HPs derivatives with predictable functions.

Chemical substitution-induced conformational and physicochemical remodeling

Substitution modification, primarily targeting the ubiquitous hydroxyl groups on the polysaccharide backbone, represents the most versatile toolkit for tailoring the multifunctional profiles of HPs. By modulating intramolecular hydrogen bonding and electrostatic landscapes, the grafting of specific functional groups fundamentally remodels macromolecular chain behavior and spatial orientation.

Sulfation and phosphorylation

Sulfation and phosphorylation serve as primary strategies for modulating charge-induced spatial conformations [125, 126]. The introduction of negatively charged sulfate or phosphate moieties generates potent intramolecular electrostatic repulsion, compelling typically coiled polysaccharide chains to undergo an uncoiling transition. This conformational change reduces steric hindrance and exposes buried bioactive domains, such as RG-I clusters, thereby amplifying their binding affinity to immune cell receptors and accelerating tissue repair [127–129]. In particular, phosphorylation endows polysaccharides with bone-mimetic properties by providing specific coordination sites for calcium ions, which enhances mineral-binding affinity and osteogenic potential in bone tissue engineering [130, 131]. The functional consequences of such charge-driven conformational remodeling have been directly quantified. As summarized in a recent review, sulfated GLPs enhance T-cell proliferation by 37% compared to their native counterparts [31]. Mechanistically, this enhanced immunostimulatory activity is attributed to the increased negative charge density following sulfate introduction, which induces chain extension from a compact coiled conformation to an extended state. This conformational change exposes previously buried bioactive groups and improves multivalent binding affinity to immune cell surface receptors. This mechanistic chain, linking functional group modification to conformation change and then to enhanced activity, provides a rational basis for designing HP derivatives and moves beyond empirical trial-and-error approaches.

Carboxymethylation and acetylation

In addition to charge-induced remodeling, carboxymethylation and acetylation offer distinct pathways for fine-tuning solubility and interfacial affinity. Carboxymethylation introduces hydrophilic carboxymethyl groups that create a dense hydration shell, disrupting native crystalline regions to drastically improve water solubility and promote ROS neutralization kinetics [132]. Conversely, acetylation substitutes hydroxyl groups with hydrophobic acetyl moieties, converting purely hydrophilic polysaccharides into amphiphilic architectures and enhancing their ability to penetrate lipid-rich cellular membranes and interface with hydrophobic drug molecules [129]. A systematic study on Amana edulis polysaccharides (AEPs) clearly illustrates how these diverse substitution routes determine distinct biological outcomes. By applying different strategies to the same native backbone, researchers demonstrated that phosphorylated AEPs exhibited the most robust scavenging activity against DPPH and hydroxyl radicals, whereas sulfated versions showed superior reducing potential [126]. This evidence demonstrates that the selection of a functional group determines the therapeutic direction of the HP, guiding it toward specific applications.

Precision chain scission and MW optimization

The MW of HPs is a critical determinant of their biofunctionality. Excessive MW can lead to poor solubility and low bioavailability, whereas strategic degradation can optimize activity thresholds within a desirable range. Physical degradation techniques, such as ultrasonication, microwave irradiation and subcritical water extraction, achieve precision shearing of glycosidic bonds via cavitation-induced mechanical forces or high-energy localized heating. These methods generate fragments with a narrow polydispersity index while maintaining the structural integrity of core bioactive repeating units [133]. In parallel, enzymatic approaches offer high-efficiency, site-specific cleavage under mild conditions. This strategy is particularly effective for pectic polysaccharides, where enzymatic trimming prunes non-essential homogalacturonan regions to selectively expose RG-I domains. Such structural refinement selectively amplifies the accessibility of previously hidden side chains to PRRs (e.g. Dectin-1 or TLR4), thereby triggering superior immunomodulatory cascades [134]. A representative study on an acidic polysaccharide derived from Amomum tsao-ko employed an integrated degradation, analysis and modification approach to create an optimized derivative (ATP-4e) [135]. By strategically decreasing its MW while preserving its nonlinear branched architecture, ATP-4e exhibited enhanced conformational flexibility and immunoregulatory capacity compared to its rigid, high-MW native form. Additionally, free radical degradation can also be employed to systematically decrease the degree of polymerization, thereby improving the intestinal absorption and targeted delivery of HPs without destroying their core bioactive repeating units [105].

Functional conjugation and interfacial tailoring

The diverse functional groups on polysaccharide chains provide versatile reactive sites for further chemical conjugation, enabling their conversion into multifunctional delivery platforms [136, 137]. Selenium (Se) modification represents a prominent advancement in this field. For instance, selenium-modified polysaccharides derived from Sagittaria sagittifolia L. exhibit improved water solubility, antioxidant activity and immunomodulatory effects compared to their native form [137]. Similarly, Astragalus polysaccharide-selenium nanocomposites (APS-SeNPs) inhibited the proliferation of HepG2 liver tumor cells by reducing mitochondrial membrane potential (ΔΨm) and increasing the Bax/Bcl-2 ratio [11, 138]. These results highlight the potential of selenium-functionalized HPs as multifunctional agents with antioxidant, antitumor and immunomodulatory activities, holding considerable promise for application in tissue regeneration and pharmaceutical formulations.

Beyond bioactive conjugation, the interfacial properties of HPs can be tailored to create amphiphilic architectures for drug encapsulation. In oil-in-water emulsions, hydrophobic components can attach to the surface of oil droplets, while hydrophilic polysaccharides can serve as a strong steric barrier against droplet aggregation and pro-oxidant engagement [139, 140]. However, the strong hydrophilicity of certain polysaccharides hinders their adsorption at the oil/water interface. To overcome this challenge, the introduction of hydrophobic groups effectively improves emulsifying properties, facilitating the design of amphiphilic polysaccharides as vehicles for drug encapsulation [135]. This modification shields encapsulated therapeutic agents from pro-oxidants in the wound microenvironment while improving local drug concentration.

Furthermore, introducing reactive groups enables the transition from linear chains to 3D, stimulus-responsive networks. The introduction of reactive moieties, such as aldehyde or methacrylic acid groups, empowers HPs with the capacity for covalent or dynamic-covalent assembly. For instance, the oxidation of Bletilla striata polysaccharide (BSPMA) creates pendant aldehyde groups capable of undergoing in situ Schiff-base linkages with amino-bearing polymers, establishing a self-healing and injectable framework [141]. In parallel, methacrylation grants polysaccharides the ability to form photopolymerized dual-network hydrogels with tunable mechanical stiffness and stimulus-responsiveness [142].

To sum up, the targeted refinement of HPs offers a versatile way to fine-tune their physicochemical and biological properties, substantially broadening their biomedical applicability. Through calculated structural adjustments, polysaccharide derivatives can be engineered to possess high bioactivity, superior solubility and tailored interfacial properties, as well as self-assembly behavior. These advances provide essential groundwork for the rational design of HP-based therapy systems. Future efforts should prioritize elucidating the intricate links between structure and activity, optimizing modification techniques for enhanced controllability and safety, and clarifying the biological mechanisms underlying their efficacy. These structural tailoring capabilities and property enhancements are the driving forces behind the advanced applications of HPs in tissue regeneration.

HP-based biomaterials for tissue regeneration

Traditional Chinese HPs constitute an abundant and sustainable resource for biomedical engineering [143]. Compared to synthetic polymers, HPs offer distinct advantages as bioactive materials due to their intrinsic pharmacological activities and biocompatibility. From a functional perspective, HPs are able to protect therapeutic payloads from phagocytic clearance and enzymatic degradation, prolong systemic circulation time and enhance drug bioavailability. Furthermore, many HPs passively accumulate in target tissues through the enhanced permeability and retention effect, enabling targeted drug delivery while minimizing systemic toxicity [144, 145]. The chemical versatility of HPs, rich in functional groups, allows for precise structural modifications to engineer smart polymeric systems that respond to microenvironmental stimuli. Recent advances demonstrate the efficacy of these HP-based platforms in the controlled release of small molecules and biologics for treating inflammatory disorders, cardiovascular diseases and tissue defects [9, 146]. Rather than serving merely as inert vehicles, HPs are engineered into multifunctional carrier-effector systems (Figure 4). These platforms, ranging from macro-scale hydrogels and porous bioscaffolds to micro/nanoscale particles, as well as precision-engineered MNs and nanofibers, synergize targeted drug delivery with their intrinsic regenerative signaling to accelerate tissue repair [147–150]. By functioning simultaneously as targeted delivery vehicles and bioactive effectors, these HP-based formulations collectively underscore their growing importance in modern regenerative medicine and multifunctional therapeutics.

Figure 4.

Schematic illustration of HP-based multifunctional platforms for tissue regeneration. These carrier-effector systems not only serve as tailored vehicles for localized drug delivery but also intrinsically function as bioactive effectors to promote cellular homeostasis and tissue repair.

Macro-biomimetic hydrogels and porous scaffolds for tissue engineering

HP-based hydrogels and scaffolds have been widely applied in tissue engineering due to their inherent biocompatibility, degradability and tunable physical properties, which enable them to mimic the native ECM. In addition to traditional wound care, these materials have also been utilized as primary building blocks in bone repair, adipose tissue engineering and multi-organ regeneration by recapitulating the biochemical cues of the native environment. Rather than serving as passive space-fillers, these materials function as hydrophilic 3D networks that maintain a moist wound environment, support controlled drug release and promote tissue regeneration through hemostatic, antimicrobial and anti-inflammatory mechanisms [6, 151]. Moreover, the dense functional groups (–OH, –COOH and –NH₂) on the HP backbone facilitate the design of smart stimuli-responsive platforms capable of dynamic adaptation to pH, enzymes or temperature.

Recent breakthroughs in hydrogel engineering highlighted the use of specific HPs to enhance mechanical strength and biological functionality. For instance, an oxidized GLP (OGLP)-based double-network hydrogel (OGLP-CMC/SA) has been shown to accelerate diabetic wound healing by effectively scavenging ROS and promoting the polarization of M1 macrophages toward the M2 phenotype [27, 152]. Similarly, the incorporation of Dendrobium polysaccharides into synthetic polymers like PVA allows for the formation of reversible covalent borate ester bonds [153]. These composite hydrogels exhibit exceptional tensile capacity (>1000%) and rapid self-healing ability (<5 s), providing a robust yet dynamic scaffold for selective antibacterial activity and tissue integration.

To achieve the requirement for structural guidance and neovascularization, porous bioscaffolds derived from Amorphophallus konjac K. Koch [konjac glucomannan (KGM)] have gained increasing attention [151]. These scaffolds, fabricated via casting-freezing or lyophilization, possess highly interconnected pore structures (typically 100–300 μm) that facilitate cell attachment and oxygen diffusion. Notably, KGM-based scaffolds have been optimized for hormone-free cultured fat production and asymmetric membranes for wound dressing, demonstrating superior versatility in both soft and hard tissue engineering [152, 154]. Furthermore, KGM/silk fibroin-based biomimetic scaffolds have shown consistent efficacy in promoting vascularization [151]. These platforms overcome the limitations of conventional systems, such as poor stability, solubility and bioavailability, while their rheologically tunable storage modulus (Gʹ) enables precise matching to target tissue stiffness, thereby enhancing treatment efficacy [45, 155, 156].

Another representative system is the injectable, photo-cross-linkable composite hydrogel (OCS/NX@Cur) developed by Zhao et al. [6], which integrates oxidized APS as a controlled-release platform for curcumin-encapsulated Achyranthes bidentata supramolecular self-assemblies. This innovative approach exemplifies the construction of multifunctional therapeutic platforms through the incorporation of bioactive nanospheres into macro-scale matrices, providing a promising strategy that combines supramolecular self-assembly with natural polysaccharide scaffold design. In parallel, 3D-printed scaffolds containing APS promote neovascularization by activating the YAP/TAZ and STAT3 signaling pathways [157]. For orthopedic applications, in situ co-deposition of APS with collagen fibrils achieves intrafibrillar mineralization, mimicking the secondary structure of bone tissue and stimulating osteoblast differentiation [158]. Among various HPs, BSP has been extensively investigated for its dual functionality as both a structural scaffold and a bioactive agent. For instance, leveraging dynamic-covalent chemistry such as Schiff-base reactions, BSP-based hydrogels have been developed with diverse functionalities, including self-healing, antioxidant, antibacterial and hemostatic properties [159], as well as the ability to provide instant protection for irregular wounds by inducing M2-like macrophage transformation. Utilizing dynamic-covalent chemistry, BSP-tannic acid hydrogels exhibit exceptional self-healing, antioxidant, antibacterial and hemostatic performance [159], while oxidized BSP-based spray hydrogels provide instant protection for irregular wounds by inducing M2-like macrophage transformation [160]. Mechanistically, BSP facilitates wound repair by remodeling the wound microenvironment, upregulating VEGF and stimulating the proliferation and migration of vascular endothelial cells and fibroblasts, thereby accelerating wound healing [161, 162]. Additionally, degradation of the BSP-based scaffold releases endogenous-like oligosaccharide fragments that integrate into biochemical pathways, further accelerating the repair process.

To sum up, HP-based scaffolds function as multifunctional systems that coordinate wound healing. However, as these systems transition toward integrated, bioactive microenvironments that combine nanoparticles and stimuli-responsive networks, the design space becomes increasingly complex. This complexity is now being addressed through artificial intelligence (AI)-assisted strategies. For example, advanced 3PM (predictive, preventive and personalized medicine) strategies integrate 3D/4D printing with network pharmacology and multi-omics to optimize herbal formulations, while fuzzy mathematical methods have been successfully employed to decode the antioxidant synergism of complex decoctions within 3D-printed matrices [163, 164]. Ultimately, the combination of AI-driven material design and smart systems that automatically sense physiological conditions to release medicine on demand will drive these platforms toward intelligent, personalized tissue regeneration.

Micro-nanoscale particles and micelles

The clinical translation of hydrophobic drugs is severely hampered by poor aqueous solubility, low bioavailability and rapid systemic clearance [165]. As illustrated in Figure 2, HPs from ginseng, Ginkgo biloba, and ginger have emerged as versatile building blocks for drug delivery, offering micro/nanostructures such as microspheres, micelles and nanoparticles [151, 166]. These formulations enhance drug solubility through core-shell architectures driven by hydrophobic interactions, van der Waals forces and electrostatic assembly [167, 168].

Among these micro/nanostructures, microspheres have been extensively explored for oral and local delivery applications, particularly to address challenges such as gastric acid degradation. For gastrointestinal delivery, HPs are increasingly utilized to protect therapeutic payloads from degradation in the gastric environment. For instance, Huo et al. developed pH-responsive, colon-targeting microspheres by encapsulating phosphorylated wild ginseng polysaccharides, which precisely targeted inflamed colonic regions to alleviate ulcerative colitis (UC) via the TLR4/MYD88 pathway [166]. Additionally, the incorporation of BSP into alginate microspheres improves mucoadhesion, extending gastric retention time for oral delivery [148]. In parallel, microfluidic technology has been employed to fabricate BSP nanocomposite hydrogel microspheres (PPD-Lipo@HMs), which provide a high specific surface area and adjustable mechanical properties to accelerate angiogenesis in diabetic wounds [169].

Beyond microspheres, amphiphilic modifications enable these polymers to form stable micelles for hydrophobic drug encapsulation. For example, hydrophobically modified BSP micelles efficiently encapsulate docetaxel and reduce the reticuloendothelial system clearance [142, 169]. A novel composite system (C/B@APB@Ber) further integrates APS-based nanoparticles into a BSP-based hydrogel matrix to inhibit the ROS/NF-κB pathway, exemplifying the transition toward multifunctional, multi-scale platforms [38]. Nanoparticles based on HPs exhibit broad versatility in anti-infection, anti-inflammation and tissue regeneration. Additionally, LBP-based nanoparticles with colon-targeting functionality effectively alleviate UC symptoms [110]. Overall, by integrating polysaccharide chemistry with advanced fabrication techniques such as microfluidics, these micro-nanoscale vehicles are paving the way for more personalized and effective regenerative therapies.

Precision-engineered MNs and nanofibers

In regenerative medicine, overcoming the stratum corneum barrier remains pivotal for localized delivery. The MNs are minimally invasive systems offering a solution for transdermal bypass. Unlike first-generation synthetic MNs, which are often biologically inert, HP MNs function as active regulators of the regenerative microenvironment [170, 171].

The transformation of HPs into high-performance MNs typically employs vacuum-assisted micromolding and centrifugal casting [171, 172]. For instance, the integration of methacrylated BSPMA with chitosan methacrylate creates a reinforced network through covalent crosslinking [170]. Mechanical profiling has confirmed that these matrices achieve a piercing force of 0.63 N/needle, surpassing traditional PVA (0.34 N) or hyaluronic acid (0.32 N) counterparts [150]. This structural integrity ensures penetration without fracture, while the polysaccharide backbone leverages fluid hydration post-insertion to trigger a programmed release of the payload [173].

The therapeutic potential of these MNs lies in their multimodal regenerative impact. For example, P. notoginseng polysaccharide-based MNs act as adjuvants, activating dermal dendritic cells via TLR2/TLR4 to enhance T-cell immune responses [174]. In infected wounds, the synergistic combination of BSPMA and phytochemicals enables a coordinated healing cascade, suppressing early-stage inflammation while promoting subsequent collagen deposition and angiogenesis [170].

In parallel, electrospun nanofibers mimicking the topological structure of the ECM have shown immense potential in complex tissue regeneration. Incorporating LBP into PLGA core-shell nanofibers enhances peripheral nerve regeneration by promoting PC12 cell differentiation and Schwann cell myelination [175]. Looking forward, the integration of these precision interfaces with advanced additive manufacturing, such as 3D bioprinting, offers unprecedented spatial control. Recent studies on 3D-printed APS scaffolds confirm their ability to accelerate traumatic skin repair by activating the YAP/TAZ pathway to upregulate VEGFA, highlighting the profound regenerative capabilities of spatially organized HP matrices [157].

Discussion and future perspectives

In this review, we have summarized recent advances in the pharmacological activities, SARs, chemical modification strategies and biomedical applications of HPs. These natural glycans function not merely as passive structural materials but as bioactive carrier-effector systems that integrate drug delivery with intrinsic regenerative signaling. Although these natural glycans are known to promote tissue regeneration, the precise molecular interactions between their structures and host immune receptors remain largely unclear. Besides, the inherent structural heterogeneity of branched herbal glycans, compounded by variations in sourcing, extraction and processing, makes it difficult to ensure reproducible therapeutic outcomes. More importantly, it is still poorly characterized what the in vivo fate of these polymers is after administration, such as their degradation kinetics, tissue distribution and the biological activity of released oligosaccharide fragments. The potential long-term effects of these degradation products on cellular function and tissue homeostasis have received little attention, representing a main challenge for clinical translation.

Looking forward, computational approaches offer promising pathways to address these challenges. AI, particularly ANN models, could be harnessed to decode the glycan code by identifying specific structural features that govern receptor recognition and biological activity [113]. Such predictive tools may eventually enable the rational selection of polysaccharide sources and modification strategies tailored to specific diseases or tissue types. In parallel, molecular docking and dynamics simulations could be integrated to model polysaccharide-receptor interactions, providing mechanistic insights that are difficult to obtain experimentally [176]. Cao et al. [177] recently proposed a strategic three-stage framework for AI-driven polysaccharide research: The first stage focuses on efficiency. Machine learning models help optimize extraction, purification and processing steps. The second stage moves to mechanism‑informed hypothesis generation, where deep learning‑based quantitative SAR models, graph neural networks and interpretable modeling begin to establish quantitative links between structural features and functional properties. The third stage provides design assistance, allowing precision‑guided engineering of polysaccharide structures for specific therapeutic goals. Although initially developed for food science applications, this framework provides a readily translatable roadmap for the regenerative biomaterials field, directly addressing the trial-and-error limitations that have historically constrained HP development.

Recent technological breakthroughs are rapidly validating the feasibility of this framework. A study by Yan and colleagues demonstrated the power of integrating cryo-electron microscopy (cryo-EM) with AI for glycan structural analysis, achieving near-atomic resolution (1.8–2.2 Å) of complex, native N- and O-glycans on algal glycoproteins [178]. The development of an AI-based automated model-building tool, EModelG, in that work represents a major leap from indirect structural inference to direct, high-precision glycan modeling. Although this study focused on glycoconjugates, a system chemically distinct from the free, heterogeneous HPs reviewed here, its methodological contribution is highly instructive. It serves as a powerful proof-of-concept, demonstrating that the AI-driven decoding of complex glycan structures is no longer a distant aspiration but an imminent reality. Extending this pipeline to free polysaccharides, which have greater conformational freedom and lack a defined protein scaffold, is a logical next step toward resolving the structural heterogeneity that currently limits the standardization and rational design of HP-based biomaterials.

In parallel, a fragmentation-reassembly strategy that combines nanopore single-molecule detection with machine learning-based signal interpretation has achieved automated sequencing of complex polysaccharides for the first time [179]. This approach breaks down glycan sequencing into a computational puzzle of fragment identification and structural reassembly, conceptually analogous to next-generation DNA sequencing, and brings the long-envisioned goal of reading the glycan code closer to experimental reality.

Whether AI-driven design can faithfully simulate the complex, multivalent interactions that occur in biological microenvironments remains an open question, but early efforts in this direction are encouraging. Beyond computation, 3D bioprinting offers a tangible route to create spatially heterogeneous tissue architectures [163, 164]. Furthermore, emerging evidence suggests that future studies should focus on how HPs and their metabolites engage with subcellular organelles, such as mitochondria, lysosomes and the endoplasmic reticulum, to exert their regenerative effects. Equally important is the need to elucidate the in vivo metabolic fate of these macromolecules, including their interactions with the gut microbiota, systemic distribution and eventual elimination, all of which remain poorly understood.

Collectively, the transformation of HPs into precision biomaterials will depend on closing these mechanistic and translational gaps. By integrating advanced computational modeling, subcellular mechanistic inquiry and rigorous pharmacokinetic characterization, the field can move beyond empirical formulations toward rationally designed systems that harness the full therapeutic potential of these ancient natural products.

Funding

This review was supported by funding from the National Nature Science Foundation of China (32071326), the High Talent Project of Guangdong Province (2024TQ08Y990), the Natural Science Foundation of Guangdong Province, China (2025A1515011133, 2026A1515010466), the Science and Technology Development Fund (FDCT) of Macau SAR (File no. 0003/2025/NRP), the High-Level Talents Scientific Research Start-Up Funds of the Affiliated Hospital of Guangdong Medical University (GCC2022013), Affiliated Hospital of Guangdong Medical University “Clinical Medicine+” Basic Science and Technology Innovation Special Program (GDMULCJC2025019), the Key Projects of Guangdong Provincial Universities (2025ZDZX2026), the Science and Technology Program of Zhanjiang, China (2022A01163, 2025A501), Liaoning Provincial Science and Technology Program (General Program, 2023-MS-166).

Conflicts of interest

The authors declare no conflicts of interest.