Sulfated polysaccharides (SPs) are naturally occurring anionic polymers primarily composed of cellulose and hemicellulose, characterized by sulfate ester groups (-OSO3-) as a class of bioactive macromolecules in plant systems (11, 12). Latest studies have provided an update on the structural chemistry of the major sulfate polysaccharides, including the galactans (e.g., agarans and carrageenans), ulvans, and fucans. SPs have demonstrated numerous beneficial bioactivities, including antioxidant, antidiabetic, hypoglycemic, anti-inflammatory, immunomodulatory, antiviral, and anticancer effects (13). The sulfated Morinda citrifolia (14) and Chinese yam (15) polysaccharide showed the good antioxidant activity, and them up to Vc level. The SPs from Orchis chusua D. Don maintained moderately stable antioxidant and probiotic ability. Among the various bioactivities, the modulation of adaptive immunity by SPs through multiple mechanisms has been the most extensively studied. Polysaccharides from Sea buckthorn leaves (SBLPs) are sulfated polysaccharide containing uronic acid. SBLPs showed antioxidant activity and immunological activity in vitro, also had the activity of immune stimulation on RAW264.7 cell (16). SPs promote dendritic cell maturation and antigen presentation to initiate T cell responses, directly regulate T cell activation, proliferation, and differentiation while balancing T cell subsets (e.g., Th1, Th2, Th17, and Treg), stimulate B cell activation and antibody production, enhance NK cell cytotoxicity, and induce cytokine secretion (e.g., ILs, IFNs, and TNF-α) to coordinate immune responses. These combined mechanisms enhance pathogen/tumor clearance, suggesting SPs hold significant promise as adjuvants in vaccine formulations (17).

Chemical modification can improve the physicochemical and functional properties of SPs. Platycodon grandiflorum roots polysaccharides (PGPs) exhibited specific antioxidant activities through Sephacryl S-100 column elution (18). The sulfated derivative polysaccharide from Siraitia grosvenorii had the ability to scavenge DPPH radicals, hydroxyl radicals and superoxide anions, and the scavenging power tended to increase with the increase in polysaccharide concentration (19). Natural Lycium barbarum seed dreg polysaccharides by sulfation showed the highest ABTS radical scavenging and reducing power while showed better DPPH radical scavenging effect than natural polysaccharides (20). Sulfated plumula nelumbinis polysaccharide significantly increase the proliferation of RAW264.7 macrophages and improve the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) based on cell model of H₂O₂-induced oxidative damage (21). However, most studies on biological effects of SPs have been conducted in vitro or in animal models. Therefore, further research involving human subjects is imperative to confirm these effects.

The acetylated polysaccharides are characterized by that the sugar unit hydroxyl is replaced by an acetyl group (-OCOCH₃). In nature, acetylated polysaccharides are extensively distributed in plants, microorganism, and animals (22). Acetyls play an essential role in polysaccharide behaviors for various biological activities (23). In recent years, a large number of studies have shown that polysaccharides exhibit excellent antioxidant and immune activities in the presence of acetyl groups. The antioxidant activity of Litchi pericarp polysaccharide (24), Chinese yam polysaccharide (15), Cyclocarya paliurus leaves polysaccharides (25) and pumpkin polysaccharides (26) were improved after acetylation modification. Introducing acetyls into polysaccharides could significantly modify their physicochemical properties and change their biological activities, such as solubility and water-solubility. After acetylation, bitter gourd polysaccharides (27), cyperus esculentus polysaccharides (28) exhibited stronger antioxidant, anticoagulant, and immune activity. The acetylated polysaccharide from Orchis chusua D. Don displayed the best proliferation effects on Bifidobacterium adolescentis (29). Arabinose (Ara) and galactose (Gal) contents were changed, and the antioxidant activity of Cyclocarya paliurus polysaccharide (CPP0.1) was subsequently increased (30). Acetylated polysaccharides of Cyclocarya paliurus polysaccharide have immunomodulatory effects on murine macrophage RAW264.7 (31). At the molecular level, pectic polysaccharide from Cucurbita moschata Duch likely activates macrophages mechanistically through TLR4- and CR3-dependent signaling pathways, involving coordinated activation of both NF-κB and MAPKs cascades (32).

Carboxymethylated polysaccharides contain carboxymethyl (-OCH₂COOH), which can significantly enhance water solubility of native polysaccharides. This modification enables structural diversity as well as providing additional bioactivities. Carboxymethylated polysaccharides were found to exhibit antioxidant activity, anti-tumor activity, immunomodulatory activity and antibacterial activity (33). Among them, antioxidant activity has been studied more extensively. The carboxymethylated polysaccharides extracted from peony seed dreg maintained moderately stable antioxidant ability (34). Carboxymethylated Morinda citrifolia polysaccharide (14) and carboxymethylated polysaccharide from Chinese yam (15) showed the good antioxidant activity, and them up to Vc level. Carboxymethylated polysaccharide from Orchis chusua D. Don (29), carboxymethylated cushaw polysaccharide (35) and carboxymethylated cucumber polysaccharide (36) exhibit better ability to scavenge superoxide anions and hydroxyl radicals. In addition, carboxymethylation modification of relevant high degree of substitution can enhance the dendritic cells maturation-inducing function of polysaccharide from the seeds of Plantago asiatica L (37).

Carboxymethylation could effectively increase the antioxidant activities of the polysaccharide. Carboxymethylated polysaccharide from Garcinia mangostana rind showed stronger activity compared to the other three chemical modification (38). Carboxymethylated polysaccharides from blackcurrant fruits (CRNPs) possessed stronger scavenging activities on radicals (hydroxyl and superoxide radicals) and better anti-lipid peroxidation activities, as well as better protection effects on erythrocyte hemolyses in vitro compared with polysaccharide extracted from blackcurrant fruits (RNP). The activities of CRNPs were significantly enhanced with the increase of the degree of substitution (DS) (203). One study showed that both of exopolysaccharide LEP-1b and its carboxymethylated derivative CLEP-1b from a Lachnum sp ameliorated physical fatigue and extended exhaustive swimming time. Moreover, CLEP-1b demonstrated dose-dependent enhancement of anti-fatigue effects, most notably at 200 mg/kg (39). This suggests that the carboxymethylated polysaccharides can be exploited as a potential healthcare compound to combat fatigue and to boost strength. Even though many studies showed that carboxymethylation could enhance the bioactivities, the mechanisms by which the carboxylate group contributes to these bioactivities remain unclear. Further exploration of the interaction between carboxymethyl polysaccharides and body molecules will facilitate the targeted production of functional polysaccharides.

Phosphorylated polysaccharides contain phosphate groups covalently attached to their saccharide units through ester bonds (-O-PO32-), imparting unique charge and functional properties (40). Phosphorylation can reduce viscosity, improve the water solubility and biological activity of natural polysaccharides. Therefore, phosphorylated polysaccharides have attracted increasing attention owing to their antioxidant, antitumor, antiviral, immunomodulatory, and hepatoprotective effects (41). Phosphoric Onion polysaccharides (42), phosphorylated Morinda citrifolia polysaccharide (14) and phosphorylated polysaccharide from Chinese yam (15) have a good antioxidant activity, and the activity was similar to that of Vc positive control. Moreover, phosphorylated polysaccharide from Orchis chusua D. Don (SP-P) was demonstrated the highest scavenging ability on hydroxyl radical and growth-promoting activity on Lactobacillus Bulgaricus (29).

Due to their diverse bioactivities and structural modifications, phosphorylated polysaccharides are increasingly studied as targets of phosphorylation modification. The phosphorylation modification product of polysaccharide from purple sweet potato (PPSP) could significantly enhances the scavenging effects on hydroxyl radicals and superoxide anions. Additionally, it could also improve the anti-lipid peroxidation ability (43). The phosphorylated polysaccharides from peony seed dreg exhibited maximum hydroxyl radical scavenging activity and ferrous ion chelating ability as compared to native polysaccharides (34). Phosphorylated Cyclocarya paliurus polysaccharide (P-CP) significantly boosted its ability to protect cells from hydrogen peroxide-induced oxidative damage compared to the native polysaccharide (44). Phosphorylation of polysaccharide from Sanchi (Panax notoginseng) flower (45), phosphorylation modification effectively enhances Abrus cantoniensis Polysaccharides (ACP) (46), phosphorylated pumpkin polysaccharide (47), phosphorylated polysaccharides from native ginseng (48), phosphorylated garlic polysaccharide (49), phosphorylated cushaw polysaccharides (50), the antioxidant activity of phosphorylated polysaccharides is several times stronger than the unphosphorylated polysaccharide. The phosphorylated derivatives of Amana edulis polysaccharide possess higher reducing power compared with the native compound (51). Phosphorylated Radix Cyathulae officinalis Kuan polysaccharides (PRCPs) have been extensively studied in immunoregulatory activity. PRCPs not only enhance humoral immunity by elevating serum immunoglobulin levels (IgG, IgA, IgM) and promoting splenocyte proliferation, but also strengthen cellular immunity through macrophage phagocytosis activation, cytokine modulation (IFN-γ, IL-2,−4,−5,−6,−10), and T-cell subpopulation regulation (52). Furthermore, PRCPs acts as a potent adjuvant to boost vaccine efficacy by facilitating dendritic cell maturation and amplifying pathogen-specific antibody responses (53, 54). The efficacy of a drug is closely related to its structure. Although phosphorylated polysaccharides are highly active and have a wide range of effects, the structure-activity relationship and mechanism of action have not been studied extensively.

Amino polysaccharides contain amino groups, typically derived from amino sugar monomers. Chitosan is a typical and relatively extensively studied amino polysaccharide. Chitosan was widely used in food and pharmaceutical industry due to its multidimensional properties, such as biocompatibility, biodegradability, antibacterial properties and non-toxicity, muco-adhesivity, adsorption properties, etc., and thus they can be widely used in variety of areas (55–57). Chitosan and its nanocomposites have applications in drug delivery (58, 59) and carrier for fertilizer (60). Animal experiments have shown that the amino sugar/curdlan hybrid materials are promising as a new type of polysaccharide immunoadjuvants useful for cancer chemotherapy (61). The function of polysaccharides in the medical field and the mechanism of interaction with body molecules need to be further explored and studied.

It is postulated that bioactivities of polysaccharides and physicochemical properties are directly or indirectly regulated by their structure (62). By introducing groups into the polysaccharide chain through physical, biological and chemical molecular modifications, the functions and effects of polysaccharides can be better exerted (63).

The anti-fatigue activity of NMPPs is a multifaceted process involving direct enhancement of energy metabolism, reduction of fatigue-associated biomarkers, and activation of antioxidant defense systems, often through synergistic or multi-target mechanisms. Polysaccharides from Zingiber officinale (ZOPA) significantly improve glycogen storage in gastrocnemius muscles while regulating energy metabolism and reducing metabolic waste accumulation, thereby delaying fatigue onset (64). Dendrobium officinale polysaccharide (EPDO) extends forced swimming time in mice by downregulating blood lactic acid (BLA) and urea nitrogen (BUN) levels, coupled with elevated SOD activity, highlighting its dual role in metabolic regulation and oxidative stress mitigation (65). These effects are further exemplified by okra polysaccharides, which prolong swimming endurance by increasing hepatic and muscle glycogen reserves while suppressing BUN and BLA accumulation (66).

The structural specificity of NMPPs significantly influences anti-fatigue potency. Bupleurum chinense DC polysaccharide BCP-2 showed superior fatigue-alleviating effects compared with BCP-1, attributable to distinct backbone compositions and branching patterns. Both contain oligogalacturonides, but BCP-1 features a backbone of 4-β-Galp and 4,6-β-Glcp with C4-branching, whereas BCP-2 consists of 3,5-α-Araf residues branched at C3 (67). Acidic polysaccharides from Panax ginseng (e.g., WGPA-A and WSGP-S3) exhibit superior activity compared with neutral counterparts, attributed to their higher sulfate content and molecular conformation (68, 69). Such structure-activity relationships suggest that targeted modifications of polysaccharide physicochemical properties could optimize their anti-fatigue potential.

NMPPs-mediated antioxidant activity can enhance exercise capacity. Polysaccharides from Gynostemma pentaphyllum (GPP) prolong exercise endurance in mice by scavenging excess ROS and preserving skeletal muscle glycogen, highlighting their potential to counteract exercise-induced oxidative stress (70). Acerola cold-water soluble polysaccharides (ACWS) exert anti-fatigue effects in vivo, likely via ROS neutralization and energy metabolism optimization (71). Polygonatum sibiricum polysaccharide (PSP) exhibits remarkable antioxidant and anti-aging properties by reducing ROS levels and increasing antioxidant enzyme activities in skeletal muscle tissue. However, direct studies on NMPPs in post-exercise recovery remain limited, direct evidence linking polysaccharide-mediated antioxidant effects to post-exercise recovery remains sparse.

Emerging evidence also implicates gut microbiota modulation and neuroendocrine regulation in polysaccharide-mediated fatigue resistance. Astragalus polysaccharides (APs) alleviates chronic fatigue syndrome by restoring gut microbial homeostasis and metabolite profiles, while Phragmites rhizoma polysaccharide suppresses hypothalamus-pituitary-adrenal axis hyperactivation to mitigate stress-induced fatigue (72, 73). These findings collectively highlight the diverse mechanisms through which plant polysaccharides combat fatigue, ranging from molecular-level metabolic adjustments to systemic physiological adaptations, positioning them as promising candidates for improving aerobic exercise capacity and post-exercise recovery.

The antioxidant activity of NMPPs plays a pivotal role in mitigating oxidative stress through direct free radical scavenging, activation of endogenous antioxidant pathways, and modulation of gut microbiota. Garlic polysaccharide (GP), an inulin-type fructan, exhibits potent direct antioxidant activity by neutralizing reactive oxygen species (ROS) (74). Artemisia ordosica polysaccharide (AOP) demonstrates dose-dependent free radical scavenging capacity in vitro and enhances systemic antioxidant defenses in vivo by upregulating GSH-Px and SOD activities in rats (75).

Indirect antioxidant mechanisms often involve immunomodulation and gut microbiota regulation. APs enhance antioxidant responses in coral trout by improving intestinal morphology and modulating microbial communities, which synergistically reduce oxidative stress (74, 76). Mulberry leaf polysaccharide reverses cyclophosphamide-induced intestinal damage in chicks by restoring gut microbiota balance and enhancing immune-antioxidant crosstalk (77). Xylo-oligosaccharides combined with γ-irradiated APs amplify antioxidant capacity in broilers through microbiota-driven immunometabolic adaptations (78).

Notably, NMPPs frequently exhibit synergistic antioxidant effects. Date seed polysaccharide-derived selenium nanoparticles (MPS-NPs) display dual antioxidant and antibacterial properties, suggesting ROS scavenging and pathogen inhibition jointly alleviate oxidative damage (79). Additionally, LBP improves sub-health conditions in mice by simultaneously boosting antioxidant enzymes, immune function, and anti-fatigue activity, indicating interconnected pathways (80). Antioxidant capacity is a critical contributor to anti-fatigue efficacy, particularly given the excessive free radical generation during prolonged exercise. Lycium barbarum polysaccharide (LBP) and Panax ginseng acidic polysaccharide (WGPA) exhibit potent antioxidant effects, enhancing SOD activity and alleviating oxidative damage (81, 82). Notably, Polygonatum kingianum polysaccharides (PKPs) ameliorate fatigue by activating the NRF2/HO-1/NQO1 pathway, which synergistically enhances antioxidant defenses and mitochondrial biogenesis via AMPK/PGC-1α/TFAM signaling (83). This dual modulation of redox balance and energy metabolism underscores the potential of polysaccharides to accelerate post-exercise recovery by counteracting exercise-induced oxidative stress.

The anti-inflammatory properties of NMPPs have been extensively investigated, demonstrating therapeutic potential in diverse inflammatory diseases through modulation of inflammatory signaling pathways and immune cell functions. In hepatic fibrosis models, GLP further inhibits hepatic stellate cell activation and extracellular matrix deposition by targeting TGF-β/Smad signaling, while regulating inflammation-, apoptosis-, and cell cycle-related proteins (84). APs mitigate lipopolysaccharide (LPS)-induced systemic inflammation by blocking NF-κB/MAPK signaling (85).

Notably, the anti-inflammatory effects of polysaccharides are closely linked to their regulation of the gut microenvironment. Rattan Pepper polysaccharide alleviates dextran sulfate sodium (DSS)-induced intestinal inflammation and depressive behavior via bidirectional modulation of the microbiota-gut-brain axis, mediated by gut microbiota remodeling and reduced inflammatory mediators (e.g., IL-1β, IL-6) (86). Likewise, Abelmoschus manihot polysaccharide enhances intestinal mucus barrier integrity by promoting the abundance of Akkermansia muciniphila, thereby attenuating intestinal inflammation (87). Additionally, Ephedrae Herba polysaccharide suppresses ovalbumin (OVA)-induced asthmatic airway inflammation by restoring the Th1/Th2 and Th17/Treg immune balance (88).

At the molecular level, polysaccharides predominantly exert anti-inflammatory effects by inhibiting key pathways such as NF-κB and TLR4. RG-I pectin-like polysaccharide from Rosa chinensis alleviates non-alcoholic steatohepatitis-related inflammation and fibrosis by disrupting HMGB1/TLR4/NF-κB signaling (89). Colon-targeted modified ginseng polysaccharides significantly reduce pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and suppress NF-κBp65/TRAF6 signaling (90). Hippophae rhamnoides polysaccharides (HRP) further protect intestinal barrier function by upregulating tight junction proteins (occludin, claudin-1) and mitigating inflammatory mediators (91). NF-κB, as a transcription factor, plays an important role in the regulation of proinflammatory cytokines such as TNF-α, IL-1, IL-6, and IL-8 (92). Moreover, Moreover, immune adaptations was related to physical improvement (93).

NMPPs mediate diverse immunomodulatory activities via direct cellular interactions, indirect signaling cascades, and synergistic effects. Direct immunomodulation is often mediated by enhancing immune cell activity or cytokine production. Sophora cassia polysaccharides significantly enhance B-cell and T-cell lymphocyte proliferation, indicating their potential to strengthen physical immunity (94). Hippophae rhamnoides polysaccharide (HRP) and Apocynum venetum flower polysaccharide (AVFP) demonstrate strong immune-enhancing effects in vitro and in vivo, likely by activating macrophages and lymphocytes (91, 95). A fructan-type GP further upregulates immune responses in macrophages and immunosuppressed mice, suggesting its role in restoring immune homeostasis (96). Additionally, polysaccharides from Areca catechu L. inflorescence effectively modulate immune responses in peripheral blood and spleen, emphasizing their systemic immunoregulatory capacity (97).

Indirect immunomodulation frequently involves interactions with the gut microbiota and intestinal immunity. Dendrobium officinale polysaccharide (DOP) and APs regulate macrophage and lymphocyte functions while improving intestinal barrier integrity and microbiota composition, thereby amplifying immune defenses (76, 98). Yupingfeng polysaccharides enhance intestinal health in Macrobrachium rosenbergii by fortifying immunity, barrier function, and microbial balance in low-fishmeal diets (99). Floccularia luteovirens polysaccharides activate the immune system in immunosuppressed mice by reshaping gut microbiota and fecal metabolites (100).

Synergistic mechanisms combining antioxidant and immunomodulatory effects are also prominent. Mulberry leaf polysaccharide alleviates cyclophosphamide-induced intestinal damage and growth inhibition in chicks by simultaneously boosting antioxidant capacity, immune regulation, and microbiota modulation (77). APs enhances coral trout growth and immunity by improving antioxidant responses and intestinal microbiota (101). Notably, xylo-oligosaccharides and γ-irradiated APs synergistically enhance immune responses and antioxidant capacity in broilers, highlighting the interplay between redox balance and immune activation (78). Additionally, Ficus carica polysaccharide (FCPs) mitigate oxidative stress via ROS scavenging while enhancing hepatic glucose metabolism and dendritic cell-driven IL-6/IL-12 production, positioning it as a multifunctional phytochemical candidate for metabolic-immune axis modulation (102).

Furthermore, polysaccharides such as Ephedra sinica polysaccharide (ESP) and Rehmannia glutinosa polysaccharide (RGP) modulate mucosal immunity by reducing pro-inflammatory cytokines, protecting intestinal barriers, and balancing microbiota-immune crosstalk, offering potential strategies to mitigate exercise-induced gastrointestinal stress (103, 104). These findings underscore the multifaceted immunomodulatory roles of plant polysaccharides, positioning them as promising candidates for improving exercise resilience through immune and metabolic optimization.

The modulation of gut microbiota represents a key mechanism by which natural medicinal plant polysaccharides influence host health, acting through both direct microbial interactions and indirect host-mediated pathways. Zingiber officinale derived polysaccharides (ZOPA and ZOPA-1) directly enhance intestinal flora diversity, alter microbial abundance, and regulate short chain fatty acid (SCFA) concentrations, potentially mediating anti-fatigue effects through the gut-muscle axis (64). Ethanol precipitated polysaccharides from Dendrobium officinale (EPDO-60) restores oxidative-antioxidative balance and accelerates fatigue metabolite clearance by reshaping gut microbial community structure (65). These direct modulatory effects are often coupled with indirect mechanisms. Green radish polysaccharides and vinegar-processed Schisandra chinensis polysaccharide ameliorate hyperlipidemia and type 2 diabetes by promoting SCFAs production and regulating microbial composition, thereby improving metabolic homeostasis (105, 106). SCFAs, as critical metabolites, not only enhance intestinal barrier function but also serve as energy substrates for skeletal muscles, suggesting a potential link to aerobic exercise recovery by mitigating exercise-induced energy depletion.

Structural specificity also dictates functional outcomes. Steaming duration alters Polygonatum cyrtonema polysaccharide (PCP) molecular weight and monosaccharide composition, thereby diversifying their digestion, absorption, and fermentation characteristics by gut microbiota (107). Xylo-oligosaccharides combined with γ-irradiated APs synergistically enhance antioxidant capacity and microbiota composition in broilers (78), emphasizing the importance of structural optimization for targeted efficacy.

Some polysaccharides exert synergistic effects through multi-target pathways. PKPs alleviate fatigue by simultaneously activating NRF2/HO-1/NQO1 and AMPK/PGC-1α/TFAM signaling pathways while modulating gut microbiota (83). Similarly, APs improve chronic fatigue syndrome by regulating gut microbiota and metabolites, highlighting a microbiota-metabolite-axis crosstalk (73). This dual regulation underscores the interconnected roles of microbial balance and host signaling in enhancing physiological resilience.

Antioxidant and anti-inflammatory activities further link gut microbiota modulation to aerobic exercise adaptation. MPS-NPs exhibit dose-dependent antioxidant and antibacterial effects (79), while acid-assisted Asparagus cochinchinensis polysaccharides protect against neurodegeneration via the microbiota-gut-brain axis (108). Since intense exercise generates excessive ROS, polysaccharides with ROS-scavenging properties, such as AOP (75), may accelerate post-exercise recovery by neutralizing oxidative stress.

Emerging evidence suggests cross-tissue communication mediated by gut microbiota. PCPY-1, a homogeneous polysaccharide from Polygonatum cyrtonema, alleviates fatigue in exhausted mice by enhancing osteocalcin-mediated bone-muscle crosstalk, thereby promoting muscle energy metabolism and ATP generation (109). This highlights the potential of polysaccharides to bridge gut microbial modulation with systemic energy regulation, a mechanism highly relevant to aerobic endurance. Nevertheless, translational studies are required to validate these findings in exercise models, particularly regarding fatigue mitigation and performance enhancement.

Natural medicinal plant polysaccharides counteract hyperglycemia and hyperlipidemia by targeting metabolic pathways directly and leveraging gut microbiota-dependent mechanisms, with synergistic actions increasingly recognized. Direct regulation of glucose and lipid metabolism is often mediated by targeting key signaling pathways. Rhizoma Ligustici Chuanxiong polysaccharides (RLMP) enhance hepatic glucose uptake and suppress oxidative stress by activating the PI3K/Akt/GLUT-4 pathway, thereby reducing hyperglycemia in diabetic models (110). PSP improve insulin sensitivity, reduce glycated serum protein levels, and normalize lipid metabolism in T2DM mice, directly alleviating hyperglycemia and dyslipidemia (111). Astragalus membranaceus polysaccharides (AMP) further demonstrate direct anti-diabetic effects by restoring pancreatic β-cell function and inhibiting hepatic gluconeogenesis (112).

Due to the limited intestinal absorption of high-molecular-weight polysaccharides, their systemic benefits frequently rely on gut microbiota-mediated metabolic reprogramming. Ulva lactuca polysaccharides mitigate aging-associated hyperglycemia in diabetic mice by reshaping gut microbiota composition and promoting the production of SCFAs, which enhance insulin signaling and suppress systemic inflammation (113). Ficus carica polysaccharides, obtained via ultrasound-assisted extraction, ameliorate oxidative stress and immunomodulatory imbalances, likely through microbiota-dependent pathways involving bacterial metabolite interactions (102). Green radish polysaccharides alleviate diet-induced hyperlipidemia by enriching beneficial gut bacteria (e.g., Lactobacillus) and stimulating SCFA production, which suppresses hepatic lipid accumulation (106). These studies underscore the pivotal role of gut microbiota in translating polysaccharide structures into metabolic benefits.

Notably, certain polysaccharides exhibit synergistic mechanisms by combining direct metabolic effects with microbiota-dependent regulation. Okra polysaccharides alleviate T2DM by directly activating the PI3K/AKT/GSK3β-Nrf2 pathway to reduce oxidative stress while simultaneously modulating gut microbial ecology to improve glucose homeostasis (114). Such multi-target actions highlight the potential of polysaccharides to address complex metabolic disorders through complementary pathways. Although current research focuses on diabetes and hyperlipidemia, the antioxidant and anti-inflammatory properties of these polysaccharides may indirectly enhance aerobic exercise capacity. Exercise-induced oxidative stress and inflammation could be mitigated by polysaccharide-mediated free radical scavenging, potentially accelerating post-exercise recovery. However, more studies are needed to further explore the cross-mechanism interactions.

Multifaceted antitumor properties of NMPPs arise from direct cytostatic/cytotoxic actions, indirect immune modulation and signaling pathway interference, and synergistic interplay often involving gut microbiota. A growing body of evidence highlights their ability to directly inhibit tumor cell proliferation and induce apoptosis. DOP suppress MNNG-induced precancerous lesions by regulating the Wnt/β-catenin pathway and altering endogenous metabolites (115). Similarly, APs inhibit tumor progression in prostate, liver, and non-small-cell lung cancers by suppressing cell growth, invasion, and enhancing apoptosis, while also improving chemosensitivity and immunity (116). Crocus sativus petal polysaccharides further demonstrate antitumor efficacy by remodeling the tumor microenvironment (TME) (117).

Indirect mechanisms often involve immune enhancement and gut microbiota modulation. Glycyrrhiza polysaccharides activate γδT cell-mediated antitumor responses via the TLRs/NF-κB pathway and gut microbiota interactions in murine models (118). A cold-water extracted polysaccharide-protein complex from Grifola frondosa exerts antitumor effects in H22 tumor-bearing mice by activating TLR4-NF-κB signaling and modifying gut microbiota composition (119). Codonopsis polysaccharides synergize with doxorubicin (DOX) to amplify tumor-killing effects and immune regulation (120).

Notably, gut microbiota-mediated pathways are a recurring theme. Reviews underscore that natural polysaccharides target gut microbiota to exert antitumor effects (121, 122). This aligns with broader evidence that polysaccharides modulate microbial metabolites, which in turn influence systemic immunity and inflammation—processes also critical in mitigating oxidative stress.

In addition to the well-documented bioactivities, natural medicinal plant polysaccharides exhibit diverse physiological effects, including anti-aging, and antidepressant activities, often mediated through gut microbiota modulation. Similarly, a water-soluble polysaccharide from Ginkgo biloba leaves exerts antidepressant activity by regulating the gut microbiome and its associated metabolites, suggesting a potential role in alleviating psychological stress through microbiota-gut-brain axis interactions (123).

These findings underscore the systemic and multifaceted roles of polysaccharides in promoting holistic health. While direct evidence linking these activities to aerobic exercise enhancement remains limited, their capacity to improve metabolic regulation, reduce oxidative damage, and modulate neuropsychiatric states may indirectly support exercise performance and recovery. Nevertheless, further studies are warranted to explore these potential cross-domain benefits and elucidate the mechanistic connections between polysaccharide modulation and aerobic capacity optimization.

NMPPs exhibit multifaceted bioactivities through multi-target and multi-pathway mechanisms, with their structural features dictating functional specificity. Through systematic induction and analysis, we have unveiled the extensive sources and diverse functions of these polysaccharides. Closely related to physiological foundations, these pathways enable medicinal plant polysaccharides to significantly ameliorate pathological states and enhance physiological conditions. These findings not only highlight their potential as supplements but also underscore their vast application value in modern medicine. Consequently, the role of medicinal plant polysaccharides as multifunctional natural supplements in the prevention and treatment of a variety of diseases cannot be overlooked, and their research and application prospects are promising. The biological activity of polysaccharides from natural medicinal plants is shown in Figure 1.

Table 1 provides a summary of the study on classification and biological activities of NMPPs.

The composition and function of intestinal microbiota are important in energy metabolism homeostasis, and polysaccharides from natural medicinal plants can improve aerobic exercise ability by regulating the composition of gut microbiota. Many studies have shown that the structure, abundance, diversity in the intestine mediate the effect of polysaccharides from natural medicinal plants on aerobic exercise ability. Polysaccharides such as ZOPA and ZOPA-1 have been shown to modulate the intestinal flora of mice, increasing diversity, altering abundance, regulating short-chain fatty acid concentrations, and enhancing antioxidant capacity through the gut-muscle axis, extending the time of exhaustive swimming in mice (64). Moreover, Ginseng polysaccharides could regulate the gut microbiota composition and promote M2 macrophage polarization by modulating TLR4/MYD88 signaling (90).

Changes in the beneficial and harmful bacteria in the intestinal flora are also important factors for the influence of NMPPs on aerobic exercise ability through the intestinal muscle axis. Polysaccharides from Dendrobium officinale (EPDO-60) modulates gut microbiota community structure by increasing proportions of Bacteroidetes and Firmicutes and abundance of Lactobacillus and Bifidobacterium in gut microbiota, thereby enhancing redox homeostasis and accelerating fatigue-related metabolite clearance (65). HRP promotes beneficial bacteria like Clostridia_UCG-014, Lachnospiraceae and suppressed pathogens such as Atopostipes, Desulfobacterot, which is crucial in HRP-mediated immunity regulation via TRAF6/NF-κB signaling, up-regulated the expression of occludin, claudin-1, and zona occludens-1 (ZO-1) (91). The GRP supplement modulated the Firmicutes/Mycobacteria ratio and Blautia spp., significantly reducing oxidative stress and inflammation in the liver of mice fed a high-fat diet (106). PKPs can reduce the number of harmful bacteria (g_Escherichia-Shigella and g_Helicobacter), while increasing the production of antioxidant bacteria (g_norank_f_Muribaculaceae) and short-chain fatty acids (SCFA), and significantly enhance exhaustive swimming time (83).

In addition to directly affecting the structure of intestinal flora, polysaccharides from natural medicinal plants can also improve aerobic exercise ability through the metabolites of intestinal flora. SCFAs are significant metabolites produced by gut microbiota during the fermentation of NMPP. A study showed that APs induced SCFAs generation and consequently reversing Nrf2/NF-κB signaling dysregulation in the brain-gut axis, which may be a key mechanism for ameliorating chronic fatigue syndrome-related metabolic disturbances (73). SCFAs also enhanced by ACP to modulate the microbe-gut-brain axis, increasing the lactic acid levels in colon contents, the abundance of Bacteroides while reducing Firmicutes and other harmful bacteria (108). Furthermore, multiple polysaccharides (e.g., FAPs, PKPs) enhanced SCFA production, linking microbial SCFA production to muscle energy optimization and improving gut barrier integrity and energy homeostasis (83, 162). MPS-NPs maintained Firmicutes/Bacteroidetes ratio and upregulated SCFA biosynthesis, such as butyrate production, which plays a critical role in maintaining gut health and energy homeostasis, supporting gut barrier integrity and muscle ATP production (79). Butyrate also mediated antioxidant and anti-inflammatory effects in neurons, linking gut ecology to systemic immunity (73). These findings position the gut as a metabolic orchestrator of muscle resilience (163). The enhanced SCFAs by AVFP is correlated with the increased beneficial bacteria, reduced harmful species, modulated immune responses through NF-κB signaling pathway, and improved the host ability to resist oxidative stress (95). In addition, studies have found that DOP increases taurine and decreases 2-hydroxybutyric acid, while promoting the growth of probiotics such as Dubosiella, Bifidobacterium, and Akkermansia, which also have beneficial effects on improving aerobic exercise capacity (164).