Based on polysaccharide nanocarriers: mechanisms of bioactivity potentiation and latest research progress

Abstract

As nanoscale drug-delivery systems constructed from natural polysaccharides, polysaccharide nanocarriers combine the inherent biocompatibility, biodegradability, and diverse bioactivities of polysaccharides with the unique size effects and functional plasticity of nanomaterials. This review systematically outlines the structural characteristics and application advantages of common polysaccharide nanocarriers, including those based on chitosan, hyaluronic acid, dextran, fructan, starch, and traditional Chinese medicine. Specifically, the review highlights the mechanisms of bioactivity of these nanocarriers in terms of their antitumor effects, immunomodulatory, anti-inflammatory, and antioxidant activities, as well as neuroprotective effects. Polysaccharide nanocarriers can not only improve the therapeutic index of drugs through targeted delivery and stimuli-responsive release but also exhibit intrinsic bioactivities that synergize with the loaded drugs, enabling integrated diagnostic and therapeutic functions. Although the existing research has demonstrated the considerable potential of polysaccharide nanocarriers in treating complex diseases such as cancer, neurodegenerative disorders, and chronic inflammation, challenges in areas such as structure-activity relationship elucidation, scalable production, long-term safety evolution, and clinical translation remain unresolved. Future research should focus on identifying polysaccharide structure-activity relationships, designing intelligent carriers, and expanding interdisciplinary applications to advance the applications of these nanocarriers in precision medicine and the biomedical field.

1 Introduction

Polysaccharides possess unique advantages when fabricated into nanocarriers, owing to their good biocompatibility, controllable structural modifiability, and excellent active substance-loading capacity (Kou et al., 2024). In comparison with synthetic polymers, natural polysaccharides possess irreplaceable biological advantages. The most polysaccharides can be gradually decomposed into monosaccharides or oligosaccharides by enzymes in the body, eventually participating in metabolic cycles without causing major toxic adverse reactions (Fu and Shi, 2024). Additionally, polysaccharides show bioactivity and multifunctionality; they act as carrier backbones and exert effects such as immunomodulation, antioxidation, and neuroprotection, providing the foundation for potential synergistic interactions between carriers and drugs (Fernandes and Coimbra, 2023).As hyaluronic acid (HA), a natural polysaccharide ubiquitously present in biological systems, not only enables precise targeting via CD44 receptors highly expressed on tumor cell surfaces, but also enhances nanoparticle dispersity and colloidal stability while reducing carrier system biotoxicity. Moreover, its biodegradation products (monosaccharides or oligosaccharides) can be metabolized by the organism, eliminating accumulation risk (Xia et al., 2025).However, some polysaccharides exhibit limitations such as poor solubility, insufficient stability, and weak targeting ability. For example, natural chitosan tends to aggregate under neutral pH conditions, and free fucoidan has a half-life of only 1-2 h in in vivo circulation (Haggag et al., 2023). Nanotechnological intervention further amplifies the advantages of polysaccharides: through precise regulation of nanoscale structures, polysaccharides can be composite with inorganic nanomaterials and functional molecules to construct integrated platforms that concurrently achieve stimuli-responsive drug release, multimodal imaging, and synergistic therapy. Such polysaccharide-based nanocarriers can not only circumvent the biosafety risks associated with inorganic nanomaterials, but also optimize carrier dispersity, stability, and targeting capability through the structural tunability of polysaccharides, effectively addressing core challenges in glioma therapy such as low drug delivery efficiency, high off-target toxicity, and monotherapeutic limitations (Li et al., 2022).

The existing biomedical nanocarriers can be mainly categorized into four types: synthetic polymers, liposomes, inorganic nanoparticles, and natural biomacromolecule-based nanocarriers (Gorain et al., 2023). Among these, natural polysaccharide-based nanocarriers constructed using nanotechnology have recently become a research hotspot because they integrate the unique advantages of nanoscale with the inherent biocompatibility of polysaccharides (Singh et al., 2022). This combination is not achieved by simple superposition; instead, it involves precise regulation of the structure and properties of polysaccharides through nanotechnology, allowing them to exhibit notable advantages in the field of drug delivery. Polysaccharides fabricated into nanocarriers using nanotechnology can show biological activity without complex chemical modification. Moreover, while retaining the characteristic complete biodegradability of polysaccharides, these nanoscale structures show safer in vivo metabolism, effectively avoiding the risk of heavy metal accumulation that may be caused by inorganic nanoparticles (Zhu et al., 2024).

Although polysaccharide nanocarriers have shown great potential, the relevant research remains ambiguous, and a systematic theoretical system and application strategy have not been established. This article aims to review the existing research on the bioactivity of polysaccharide-based nanocarriers, focusing on the pathways integrating the biological advantages of natural polysaccharides and nanotechnology. It systematically summarizes the biocompatibility, degradability, and inherent bioactivity of polysaccharides, which are attributable to their structural diversity, as well as the core properties of polysaccharide-based nanocarriers formed by combining these characteristics with nanoscale effects. The article further delves into the regulatory mechanisms of polysaccharides for carrier targeting, bioactivity, and drug-release behaviors, and reveals the adaptability of nanocarriers constructed from polysaccharides of different sources in the treatment of specific diseases. This study fills the gap regarding insufficient systematic summarization of bioactivity mechanisms: current research on polysaccharide nanocarrier bioactivity mechanisms remains fragmented, lacking systematic elucidation of both common mechanisms (e.g., biocompatibility- and degradability-related mechanisms) and specific differences (e.g., variations among different bioactivities and disease adaptabilities). By focusing on this core issue, our work addresses the fragmentation in mechanism research. This review transcends the boundaries of material types and disease domains, systematically delineating the common mechanisms and specific differences of polysaccharide nanocarriers in multiple biological activities, including anti-tumor, immunomodulatory, antioxidant, anti-inflammatory, and neuroprotective functions, thereby overcoming the fragmented limitations of existing research.

2 Classification system, construction methods, and performance characterization of polysaccharide nanocarriers

As natural biomacromolecules, polysaccharides combine excellent mechanical strength, biocompatibility, and structural tunability, while their unique architecture provides efficient stress-dispersion sites within materials, making them ideal candidates for reinforcing polymer matrix performance (Cao et al., 2024); polysaccharide nanocarriers are a class of submicron (particle size typically less than 1,000 nm) drug-delivery systems prepared using natural polysaccharides or their derivatives as core raw materials. The distinguishing features of these nanocarriers encompass the encapsulation, loading, or binding of drugs through long monosaccharide chains (linked by glycosidic bonds in polysaccharide molecules) and functional groups, thereby optimizing the drug-delivery process (Zhang et al., 2023). These nanocarriers can be added as functional ingredients to foods and dietary supplements, and they have shown highly promising application prospects in fields such as food nutrition enhancement, targeted drug delivery, protection of bioactive substances, and neuroprotection (Figure 1). The classification of polysaccharide nanocarriers is not solely based on particle size; instead, it mainly relies on structural characteristics and drug-delivery forms. Polysaccharide nanoparticles (including nanospheres) are solid microparticle structures formed by polysaccharide molecules through physical crosslinking, chemical polymerization, or electrostatic interaction, with the drugs mostly loaded inside or on the surface of the particles through physical encapsulation, surface adsorption, or chemical bonding. Polysaccharide nanomicelles are typically self-assembled through amphiphilic polysaccharides in aqueous media to form a core-shell structure, wherein hydrophobic drugs are primarily embedded in the core while the shell comprises hydrophilic polysaccharide chains, which can improve the water solubility and biocompatibility of the carrier (Plucinski et al., 2021). Polysaccharide nanovesicles are nanocarriers with a hollow vesicular structure that consist of a bilayer or multilayer membrane (formed by polysaccharides or their derivatives) enclosing an internal aqueous cavity, and the drugs can be dissolved or dispersed in the cavity or adsorbed on the membrane surface. Polysaccharide-based composite nanocarriers are constructed by compounding polysaccharides with other functional materials; moreover, as polysaccharides themselves have certain therapeutic effects, compounding them with other functional materials to form such carriers overcomes the limitations of single polysaccharide carriers through a multi-component composite structure and further enhances the overall therapeutic effect by leveraging the synergistic effects between materials (Yan et al., 2024).

FIGURE 1

2.1 Common types of polysaccharide-based nanocarriers

The biological activity of polysaccharide nanocarriers stems from their specific structures. The distribution characteristics of repeated sugar-unit backbones and functional groups such as hydroxyl, amino, and carboxyl groups in common polysaccharides form the structural basis for their core carrier properties, including biocompatibility and modifiability, and determine the differences in water solubility, charge properties, and targeting capabilities among various polysaccharides, providing structural support for understanding their functional mechanisms in drug-delivery systems (Figure 2).

FIGURE 2

Wang S. L. et al., 2025).

2.1.1 Chitosan

Chitosan is a natural cationic polysaccharide rich in functional groups such as amino and hydroxyl moieties. It exhibits favorable interactions with tissues and cells in vivo while demonstrating excellent pH tolerance, maintaining relatively stable structures under both acidic and neutral conditions. Due to these characteristics, chitosan offers significant advantages in oral drug delivery systems, capable of protecting drugs and maintaining their stability within the complex gastrointestinal environment to achieve targeted delivery (Zhang J. M. S. et al., 2025).

Studies on chitosan-based nanocarriers have demonstrated that, leveraging its cationic nature, chitosan can efficiently load negatively charged drug molecules and nucleic acids via electrostatic interactions. Simultaneously, chitosan enhances drug mucoadhesion, prolonging gastrointestinal residence time and thereby improving oral bioavailability (Liu X. D. et al., 2024). Modulating the network structure density of chitosan-based nanocarriers enables sustained controlled release of loaded drugs, avoiding toxicity from burst release while maintaining prolonged therapeutic concentrations (He et al., 2025). Research in gene delivery has confirmed that chitosan can form stable complexes with DNA or RNA, effectively protecting nucleic acids from enzymatic degradation and promoting their cellular uptake. Consequently, chitosan-based nanocarriers serve as reliable tools for gene therapy, demonstrating broad potential in genetic intervention studies for various diseases.

The realization of these advantages fundamentally relies on the reactivity of the C2-position amino group and C3/C6-position hydroxyl groups in chitosan molecules. Under acidic conditions, the amino groups can be protonated to form positively charged -NH₃⁺, which creates ionic bonds with anionic crosslinkers or polyanionic drugs/nucleic acids through electrostatic interactions, while hydroxyl groups assist in structural stabilization via hydrogen bonding. In covalent crosslinking approaches, amino and hydroxyl groups can also form covalent linkages such as Schiff base bonds and lactam bonds with crosslinkers like glutaraldehyde and genipin. Combined with non-covalent interactions (e.g., hydrophobic interactions, van der Waals forces) during self-assembly, chitosan molecules are ultimately crosslinked, complexed, or spontaneously aggregated into stable nanostructures such as nanospheres and nanocapsules, providing the structural foundation for efficient drug loading, targeted delivery, and controlled release (Nawaz et al., 2025).

2.1.2 Hyaluronic acid

Hyaluronic acid (HA) is a linear acidic mucopolysaccharide ubiquitously present in human tissues, composed of repeating D-glucuronic acid and N-acetyl-D-glucosamine units linked via alternating β-(1→3) and β-(1→4) glycosidic bonds. Its molecular chain is rich in functional groups including hydroxyl (-OH), carboxyl (-COOH), and acetamido (-NHCOCH₃) moieties (Gao et al., 2022). HA can be progressively degraded into small molecule fragments, exhibits excellent biocompatibility, and does not induce long-term toxic side effects (Kong et al., 2024).

HA-mediated CD44 receptor targeting fundamentally relies on the molecular recognition capability of its specific functional groups: the negatively charged carboxyl groups (-COOH) can form electrostatic interactions with basic amino acid residues in the extracellular domain of CD44 receptors, the acetamido groups (-NHCOCH₃) bind to hydrophobic groups of the receptor via hydrogen bonding, while hydroxyl groups (-OH) assist in stabilizing the ligand-receptor complex structure (Mugundhan and Mohan, 2025). This synergistic multi-functional group interaction enables HA to specifically recognize CD44 receptors overexpressed on tumor cell surfaces, triggering receptor-mediated endocytosis to achieve targeted nanocarrier delivery and providing a foundation for precision in tumor therapy (Cai et al., 2025). Based on this property, researchers constructed hyaluronic acid-cinnamaldehyde self-assembled nanomicelles (HPCNPs), wherein the loaded pheophorbide a-copper complex can accumulate at tumor sites via CD44 mediation and release drugs under acidic microenvironment stimulation, inducing immunogenic cell death through ROS generation, glutathione depletion, and photodynamic-chemodynamic synergistic effects. When combined with α-PD-L1, this approach effectively ablated primary tumors and inhibited distant metastasis (Zhang et al., 2024).

Beyond CD44-mediated targeting, HA serves multi-functional roles in polysaccharide-based nanocarrier applications: In antimicrobial drug delivery, HA can conjugate with antibacterial components (e.g., antimicrobial peptides, zinc oxide nanoparticles) via Michael addition or amidation reactions to construct responsive nanoformulations. ABOHA@ZnO hydrogel microspheres can release antimicrobial peptides under acidic environments induced by bacterial infection and hyaluronidase action, demonstrating significant antibacterial activity against Staphylococcus aureus (including MRSA) while inhibiting biofilm formation (Lin et al., 2025); HA-grafted polydopamine (PDA-HA) nanoparticles achieve photothermal sterilization under near-infrared irradiation, exhibiting 100% antibacterial efficacy against both Gram-positive and Gram-negative bacteria (Li et al., 2025a). In tissue regeneration and regenerative medicine, HA-based hydrogels can mimic the three-dimensional network structure of extracellular matrix, promoting osteogenic differentiation of bone marrow stromal cells and enhancing bone defect repair efficiency by modulating PI3K-AKT and MAPK signaling pathways, while simultaneously reducing inflammatory responses by inducing macrophage polarization toward the M2 phenotype. In wound dressing applications, HA derivatives composed with collagen, dopamine, and other components form hydrogels that accelerate skin injury healing by modulating the inflammatory microenvironment and promoting angiogenesis (Zhang et al., 2024). Additionally, HA can modify lipid nanocarriers through covalent bonds or electrostatic interactions to improve biocompatibility and targeting capability for glioblastoma therapy across the blood-brain barrier, significantly enhancing drug enrichment at tumor sites and prolonging animal survival time (Mendes et al., 2025).

2.1.3 Dextran

Dextran is a natural polymer formed by →3)-β-d-Glcp-(1→, →4)-β-d-Glcp-(1→, →6)-glycosidic bonds. The structural differences in glycosidic linkage directly determine the solubility, molecular-weight characteristics, and bioactivity potential of dextran (Ameri Shah et al., 2025). These structural features provide the fundamental basis for the formation, stability maintenance, and functional performance of dextran-based nanocarriers, attracting significant attention in drug delivery and cancer therapy.

The construction of dextran-based nanocarriers fundamentally relies on its structural characteristics and functional group reactivity. The hydroxyl groups, as key functional moieties, facilitate molecular self-assembly through hydrogen-bonding interactions while providing sites for chemical modification. By grafting hydrophobic groups, functional molecules, or inorganic nanoparticles onto dextran, amphiphilicity or specific reactivity can be imparted, enabling spontaneous assembly into core-shell nanomicelles or nanoparticles (Prithviraj, 2024). Specifically, the branched structure dominated by →6)-glycosidic bonds enhances molecular flexibility, favoring the formation of dense nanocore-shell architectures that encapsulate hydrophobic drugs within the core while the hydrophilic hydroxyl groups constitute a shell layer that reduces aggregation propensity in aqueous physiological environments, ensuring dispersive stability (Liu Q. et al., 2024). Moreover, dextran’s molecular weight can be tuned through enzymatic or chemical modification of glycosidic bonds, thereby optimizing the nanocarrier’s in vivo circulation time and biodegradation rate—low-molecular-weight dextran (<40 kDa) more readily penetrates biological barriers, whereas high-molecular-weight dextran enhances tumor accumulation efficiency through prolonged circulation (Ameri Shah et al., 2025).

Regarding stability and biological performance, dextran’s structural features play pivotal roles: the hydrogen-bonding networks formed by its hydroxyl groups enhance environmental stress tolerance to stimuli such as pH and oxidation (e.g., dextran-modified cerium oxide nanoparticles maintain good dispersibility after 6-month storage through synergistic effects between hydroxyl groups and Ce³⁺/Ce⁴⁺ redox cycling) (Yan et al., 2025). These features also enable regulation of biological activity via electrostatic or hydrogen-bonding interactions with immune cell surface receptors, such as modulating macrophage polarization to control pro-/anti-inflammatory cytokine expression for immunomodulatory and anti-inflammatory synergy (Hu et al., 2021). In cancer therapy, the glycosidic bond architecture and hydroxyl modifications mediate multitarget effects—the →3)-glycosidic bonds in branched structures enhance tumor cell apoptosis induction, while →6)-glycosidic bonds facilitate carrier degradation by enzymes in the tumor microenvironment for controlled drug release. Synergy with chemo/radiotherapy and targeted therapy enhances anticancer efficacy through mechanisms including augmented drug cellular uptake and inhibition of tumor angiogenesis (He et al., 2023). Representative applications include quercetin-loaded dual-grafted dextran nanomicelles, where hydrophobic groups and functional fragments are grafted onto dextran chains, leveraging hydroxyl hydrophilicity to maintain micelle dispersion stability while enhancing quercetin loading via hydrophobic interactions, ultimately significantly improving antioxidant/anti-inflammatory activities and cellular uptake efficiency (Plucinski et al., 2021). Furthermore, dextran can serve as a coating material to modify other nanocarriers—for instance, when decorating albumin nanoparticles, its abundant surface hydroxyl groups form multiple hydrogen-bonding networks with amino, carboxyl, and hydroxyl groups on the albumin surface, supplemented by weak hydrophobic interactions between albumin’s hydrophobic domains and dextran’s glucose ring skeleton, plus electrostatic complementarity between dextran’s weak negative charge from hydroxyl dissociation and the negative surface potential of albumin particles. This effectively circumvents intermolecular electrostatic repulsion, achieving stable non-covalent conjugation while enhancing tumor drug enrichment and reducing systemic toxicity (Pangua et al., 2025).

2.1.4 Fructan

Fructans are natural polysaccharides composed of fructose residues linked primarily by β-(2→6) glycosidic bonds in the main chain, with some containing β-(2→1) branching structures. The densely distributed hydroxyl (-OH) groups and specific glycosidic bond patterns in their molecular chains constitute the structural foundation for their core functions as nanocarriers. These features directly regulate nanocarrier formation, stability, responsiveness, and biological performance, endowing fructans with unique advantages in drug delivery (Tornacı et al., 2025).

Fructans can self-assemble into nanoparticles without additional surfactants, relying on the synergistic interplay between their structural characteristics and functional groups. The hydroxyl groups on the molecular chain can form dense intra- and intermolecular hydrogen bonds, providing the core driving force for self-assembly and promoting spontaneous aggregation of fructose residue-linked long chains into compact nanospheres (Wang W. J. et al., 2025). The ratio of β-(2→6) main chains to β-(2→1) branches modulates molecular flexibility and spatial conformation high branching facilitates formation of stable spherical structures, while long-chain linear fructans, due to stronger intermolecular forces, can self-assemble into uniformly sized compact particles (Plucinski et al., 2021). Solution pH further optimizes self-assembly efficiency by modulating the protonation state of hydroxyl groups: under alkaline conditions, deprotonated hydroxyls enhance intermolecular electrostatic repulsion, preventing particle aggregation and facilitating ordered, stable nanostructures; under acidic conditions, weakened hydrogen bonds lead to disordered self-assembled structures. This surfactant-free self-assembly characteristic not only simplifies carrier preparation but also avoids the cytotoxicity of exogenous surfactants, establishing a foundation for carrier biosafety (Koşarsoy, 2023).

The high stability of fructan nanocarriers originates from the degradation-resistant properties of their structure and functional groups: the spatial conformation of β-(2→6) glycosidic bonds renders them difficult to be recognized and hydrolyzed by digestive and metabolic enzymes in vivo, significantly enhancing enzyme resistance and prolonging circulation time. Simultaneously, the hydrogen-bonding network formed by hydroxyl groups further reinforces nanoparticle structure, preventing dissociation in physiological environments and providing an adequate time window for targeted drug delivery (Cao et al., 2024).

The smart-responsive functions of fructan nanocarriers can be achieved through structural modification or inherent functional group properties: introducing responsive groups enables construction of ROS-responsive systems, while the inherent protonation/deprotonation characteristics of hydroxyl groups confer pH responsiveness (Fu and Shi, 2024). The acidic microenvironment of pathological sites can alter the charge state of hydroxyl groups, disrupt the hydrogen-bonding network, and trigger carrier dissociation with precise drug release; alkaline conditions stabilize the structure, preventing premature drug leakage. For example, oleuropein-loaded fructan nanoparticles exhibit encapsulation efficiencies of 79%–92% at pH 10, gradually releasing the drug upon entering the acidic intestinal environment, effectively reducing exposure risk to normal tissues. Furthermore, through esterification to introduce 3-mercaptopropionic acid into fructan molecules, stable Au-S coordinate bonds can be formed with gold nanoparticles via thiol groups to construct functional composite carriers (AAP-SH-AuNPs). While unmodified fructans can interact with immune cell surface receptors through hydroxyl groups, the functionalized AAP-SH-AuNPs can bind to TLR4 via fructan chains, activating the TLR4/Myeloid differentiation factor 88 (MyD88)/Nuclear factor kappa B (NF-κB) signaling pathway to modulate the balance of cytokines such as IL-6 and TNF-α, thereby ameliorating immunodeficient states (Wang T. L. et al., 2025).

2.1.5 Starch

Starch is a widely sourced, low-cost plant storage polysaccharide composed of amylose and amylopectin, with hydroxyl groups (-OH) as the core functional moieties. The α-(1→4) glycosidic bonds of amylose, along with the α-(1→4) main chain and α-(1→6) branch glycosidic bonds of amylopectin, collectively determine the formation, stability, and biological performance of starch-based nanocarriers, endowing them with unique advantages in functional foods and nutritional delivery (Caldonazo et al., 2021). Amylose, a linear polysaccharide chain linked by α-(1→4) glycosidic bonds, can spontaneously fold into a single-helix structure whose internal hydrophobic cavity specifically encapsulates lipophilic bioactives such as lipids and vitamins. This process is driven by a hydrogen-bonding network formed by intramolecular hydroxyl groups, which stabilizes the helical conformation while hydrophobic interactions between the cavity and guest molecules facilitate encapsulation. The α-(1→6) branch structure of amylopectin, meanwhile, prevents excessive amylose aggregation through steric hindrance from short branch chains, regulating nanoparticle size and dispersity for instance, waxy corn starch forms nanoparticles with superior dispersity due to its high branch content (Qiu et al., 2023).

The stability of starch-based nanocarriers is directly governed by amylose content, crystalline structure, and intermolecular forces: high-amylose starch readily forms V-type crystals with lipids, and after microwave moist-heat treatment, increased single-helix content enhances V-type crystallinity, enabling nanocomposites to achieve up to 55.41% resistant starch content. This dense crystalline structure resists amylase hydrolysis, prolonging gastrointestinal circulation time (Wu et al., 2025). The hydrogen-bonding network formed by inter- and intramolecular hydroxyl groups is crucial for maintaining structural stability; in starch-lipid complexes, amylose hydroxyls form hydrogen bonds with lipid polar groups, reinforcing the single-helix encapsulation structure to prevent premature guest molecule leakage, while microwave treatment promotes molecular rearrangement to further strengthen hydrogen-bonding interactions. Furthermore, hydroxyl groups on starch chains serve as key sites for chemical modification; through esterification and etherification, hydrophobic groups can be introduced to confer amphiphilicity, enabling self-assembly into nanomicelles, vesicles, and other carriers in aqueous solutions, or forming composite nanocarriers with polyphenols and proteins via hydrogen bonding and electrostatic interactions to enhance loading efficiency of active ingredients (Yu et al., 2021).

The biological performance of starch-based nanocarriers stems from synergistic interplay between structural features and functional groups: the single-helix hydrophobic cavity of amylose physically encapsulates active ingredients, shielding them from digestive enzymes and oxidative damage, while hydrogen bonds between hydroxyl groups and polyphenols/flavonoids enhance the water solubility and stability of such components, reducing gastrointestinal degradation (Qiu et al., 2023). For example, curcumin-loaded starch nanoparticles protect curcumin from oxidation through hydrogen-bonding interactions, increasing bioavailability by over 30%. Controlled-release performance positively correlates with amylose content—high-amylose carriers achieve sustained release due to strong enzymatic resistance, while higher amylopectin content yields relatively faster release rates to meet diverse delivery requirements. Concurrently, the natural polysaccharide structure and hydroxyl groups endow carriers with excellent biocompatibility; blank starch nanoparticles exhibit >85% viability in normal cells, and their degradation products (glucose) are metabolizable by the human body, ensuring high safety (Subramani et al., 2017).

2.1.6 Traditional Chinese medicine polysaccharides (TCMP)

TCMP are a class of bioactive polysaccharides extracted from Chinese herbal medicines. The functional groups in their molecular structures, including hydroxyl (-OH), amino (-NH₂), and carboxyl (-COOH) groups—along with glycosidic bonds such as β-(1→3), α-(1→4) linkages and the degree of branching, constitute the core foundation that facilitates the formation of stable nanocarriers, confers targeting capabilities, and enables excellent biological performance (Fu and Shi, 2024). TCMP can construct nanodelivery systems through multiple approaches: On one hand, their branched structures provide abundant binding sites to form dense shells via hydrogen bonding and electrostatic interactions with active sites on carrier materials such as nano-selenium and liposomes, preventing carrier aggregation or rapid clearance while enhancing biocompatibility and dispersion stability through the polysaccharide’s hydrophilicity (Chen and Wang, 2025). On the other hand, polysaccharides can directly encapsulate active components by forming nanomicelles, nanospheres, or composite nanoparticles through self-assembly and chemical crosslinking. Among these, the multiple hydrogen bonds formed between abundant hydroxyl groups on polysaccharide molecules and carrier materials are crucial for maintaining structural stability. Polysaccharides containing amino groups can further enhance carrier compactness through coordination interactions, prolonging systemic circulation time. Polysaccharides with linear structures readily form uniform coatings on carrier surfaces, whose specific glycan sequences can be specifically recognized by surface receptors on immune cells, enhancing targeting to immune cells or tumor tissues. Highly branched polysaccharides can increase binding sites with tumor cell surface proteins through functional groups on their branch chains, thereby improving targeting enrichment capability (Liu et al., 2025).

In terms of biological performance, functional groups such as hydroxyl and carboxyl groups in polysaccharides exert antioxidant and anti-inflammatory effects by scavenging free radicals and regulating inflammatory pathways, creating synergistic effects with the antioxidant properties of nano-selenium or the delivery functions of liposomes. For example, the dense hydroxyl groups in ginger polysaccharide molecules can collaborate with nano-selenium to achieve 99.25% ABTS free radical scavenging, alleviating oxidative damage in nerve cells (Sun J. et al., 2025). Codonopsis pilosula polysaccharide, when loaded in liposomes modified with lactoferrin for blood-brain barrier targeting, can downregulate the TLR4/MyD88/NF-κB pathway to suppress neuroinflammatory factor release (An, 2022). Simultaneously, the glycan structures of TCMP can modulate immune cell functions, promoting secretion of cytokines such as IL-6 and TNF-α and enhancing immune surveillance capabilities, thereby achieving immunomodulatory and anti-tumor effects in synergy with the carrier. Moreover, TCMP polysaccharide coatings can reduce degradation of active ingredients in the gastrointestinal tract and bloodstream. Introducing hydrophobic or charged groups through modifications such as esterification and sulfonation can optimize the carrier’s hydrophilic-hydrophobic balance, enhancing penetration capability within the tumor microenvironment (Zhang S. et al., 2025).

In anti-tumor applications, mushroom polysaccharide-modified selenium nanoparticles can bind to tumor cell surface receptors through their branched structures, enter cells via endocytosis, and induce apoptosis through caspase- and mitochondria-mediated pathways (Zeng et al., 2019). The polysaccharide coating reduces the biotoxicity of nano-selenium, effectively inhibiting tumor growth in gastric cancer xenograft models without causing significant organ damage. Meanwhile, Astragalus polysaccharide, Ganoderma lucidum polysaccharide, and others can target tumor-associated macrophages (TAMs) by constructing carriers such as liposomes and nanomicelles, promoting M2-to-M1 polarization while enhancing dendritic cell maturation and activating CTL cell infiltration to remodel the tumor immune microenvironment (An et al., 2023). Additionally, traditional TCMP can enhance anti-tumor efficacy through co-delivery with chemotherapeutic drugs and immune checkpoint inhibitors. For example, co-loaded nanoparticles of lentinan and chemotherapeutic agents can augment immunotherapy response by modulating the gut microbiota (Fu and Shi, 2024).

Overall, Functional disparities among polysaccharide nanocarriers originate from their intrinsic structural features, encompassing functional groups, glycosidic bond connectivity, molecular weight/branching degree. Key characteristics and matched scenarios are summarized below: Regarding targeting mechanisms, hyaluronic acid (HA) accomplishes active targeting via CD44 receptor recognition (suitable for CD44-overexpressing tumors), outperforming chitosan’s cationic mucoadhesive targeting (suitable for gastrointestinal diseases/oral delivery). Tricholoma matsutake polysaccharides (TCMP) mediate immune targeting through immune cell receptor engagement, dextran relies on molecular weight modulation for barrier penetration/enhanced permeability and retention (EPR) effects, while fructan exhibits pH-responsive passive targeting. For drug loading and release, chitosan efficiently loads anionic drugs/nucleic acids, hydrophobically modified HA accommodates lipophilic drugs, starch amylose encapsulates lipophilic substances, TCMP complexes water-soluble drugs via hydrogen bonding, fructan demonstrates the longest release cycle (72–120 h) due to enzyme resistance, and dextran enables photoresponsive precise release. In terms of bioactivity, TCMP-nano-selenium composites show superior immunomodulatory synergy, fructan-gold nanoparticles exhibit enhanced macrophage activation capacity, chitosan-selenium demonstrates advantageous antioxidant activity, and HA composites display remarkable ROS scavenging after blood-brain barrier crossing. Concerning stability and metabolism, fructan exhibits optimal enzyme resistance and circulation half-life, starch possesses the highest biosafety, chitosan requires modification to address neutral pH aggregation, and HA is prone to hyaluronidase degradation. For disease applications, TCMP suits immunotherapy-sensitive tumors and neurodegenerative diseases, starch and fructan are appropriate for functional food fortification (low cost/toxicity), and dextran offers advantages in solid tumors requiring combined photo-/chemodynamic therapy. These comparisons elucidate the core functional distinctions among polysaccharide nanocarriers, providing direct guidance for rational design.

2.2 Methods for preparation of polysaccharide nanocarriers

The preparation methods of polysaccharide nanocarriers closely match the structural characteristics of polysaccharide molecules and the requirements of the application scenarios, centering on technical systems such as physical recombination, chemical modification, biological regulation, and composite construction (Figure 3). Figures 3A–F illustrates six preparation methods with distinct core mechanisms: Self-assembly (A) relies on the synergistic balance of hydrophobic interactions, hydrogen bonds, and other intermolecular forces in amphiphilic polysaccharide derivatives to reduce interfacial energy and form core–shell nanostructures, where structural stability depends on the dynamic equilibrium between hydrophobic aggregation and hydrophilic repulsion. Acid hydrolysis (B) protonates glycosidic bonds to induce cleavage, with short-chain fragments subsequently reassembling via hydrogen bonds and van der Waals forces; controlling the degree of hydrolysis is critical to prevent disordered aggregation. Covalent cross-linking (C) employs polysaccharide functional groups reacting with cross-linkers to form covalent bonds, constructing three-dimensional networks that lock molecular conformations, with cross-linking density governing the correlation between carrier pore size, stability, and release behavior. Graft copolymerization (D) builds amphiphilic copolymers by covalently grafting functional monomers onto polysaccharide backbones, where grafting rate and monomer ratio regulate the hydrophilic–lipophilic balance, thereby influencing self-assembly efficacy. Enzymatic catalysis (E) utilizes enzyme-specific recognition and cleavage of glycosidic bonds while preserving functional group integrity, followed by reconstitution into nanoparticles through processes such as low-temperature retrogradation. Composite construction (F) achieves synergistic effects between polysaccharides and other materials through hydrogen bonds, electrostatic interactions, or coordination bonds, where the composite ratio determines interfacial binding strength, thereby modulating carrier targeting capacity and stimuli-responsiveness.

FIGURE 3

The self-assembly of polysaccharides typically occurs at the molecular or supramolecular level. When amphiphilic polysaccharide derivatives such as carboxymethyl starch (degree of substitution, DS = 0.01–0.80) or oxidized astragalus polysaccharide (molecular weight = 5,650 Da) are introduced into an aqueous environment, the hydrophobic regions within their molecules spontaneously aggregate to form a hydrophobic core, while the hydrophilic segments (e.g., the β-(1→4)-linked glucopyranosyl backbone bearing α-(1→6)-branched side chains in astragalus polysaccharide) extend outward to bind water molecules, creating a hydrophilic shell. In this process, the amphiphilic balance of polysaccharide derivatives—including the degree of hydrophobic modification (optimal DS = 0.80 for carboxymethyl starch) and the composition of hydrophilic segments (e.g., glucose:galactose:arabinose molar ratio of 5:3:2 for astragalus polysaccharide)—serves as the critical determinant of nanoparticle morphology (Zhao et al., 2025). Excessive hydrophobic modification tends to yield rod-like or vesicular supramolecular assemblies (diameter = 2.69 ± 0.54 μm), whereas an optimal balance favors the formation of spherical micelles (particle size = 180 ± 9.4 nm, PDI = 0.3 ± 0.05). Furthermore, solution conditions—including pH (optimal pH = 7), ionic strength (NaCl concentration = 0.1–0.3 mol/L), and temperature (80 °C)—can modulate particle size, dispersity, and surface potential (zeta potential = −43.3 to −46.0 mV) by tuning intermolecular interactions. For instance, elevated ionic strength under neutral pH promotes moderate particle aggregation, thereby enhancing system stability (Zhao et al., 2025). This self-assembly arrangement significantly reduces interfacial energy, driving the autonomous formation of nanoparticles. Beyond hydrophobic interactions as the primary driving force, the process also relies on the synergistic effects of multiple intermolecular forces, including hydrogen bonds, van der Waals forces, and ionic interactions. This approach offers distinct advantages for loading polysaccharide and protein drugs, and the carrier surface potential can be regulated by adjusting material composition (Tornacı et al., 2025).

Acid hydrolysis is the hydrolysis conducted under acidic conditions. The acid type (e.g., hydrochloric, sulfuric, acetic) influences both hydrolysis rate and selectivity; strong acids exhibit high efficiency but readily cause excessive polysaccharide degradation, whereas weak acids afford milder reactions with superior product uniformity. The initial molecular weight of the polysaccharide dictates the hydrolysis difficulty, with high-molecular-weight polysaccharides requiring elevated acid concentrations or prolonged reaction times to achieve target particle sizes. Elevated reaction temperatures accelerate chemical bond cleavage, reducing particle size but potentially compromising crystallinity, while low-temperature hydrolysis, though preserving more native structures, suffers from lower efficiency (Hassan et al., 2022). It disrupts chemical bonds through protonation, promoting the decomposition of precursor molecules and their reassembly into nanostructures. Precise control of nanostructures is achievable by regulating the acid concentration, reaction time, and temperature. This method, which is widely applied in the preparation of natural polysaccharide nanoparticles, enables precise control of particle size by adjusting acid concentration and hydrolysis time—an increase in acid concentration can reduce particle size by 30%–40%. However, the pH must be strictly maintained at ≥2.0 to avoid reduction of drug-loading capacity as a result of excessive degradation (Jafernik et al., 2023).

The preparation of nanocarriers by covalent crosslinking can replace non-covalent interactions with covalent bonds to irreversibly connect carrier backbones or functional units, forming stable nanostructures. The type and concentration of crosslinking agents constitute critical determinants: chemical crosslinkers demonstrate high crosslinking efficiency, rapidly forming dense networks that enhance carrier mechanical strength, albeit with potential residual toxicity; natural crosslinkers provide superior biocompatibility but exhibit slower crosslinking kinetics, requiring compensation through increased concentration or prolonged reaction times. Reaction temperature and pH govern crosslinking reaction kinetics, thereby regulating crosslinking density. High crosslinking density reduces carrier pore size and retards degradation rate, while low crosslinking density enhances carrier flexibility and drug diffusion efficiency. Moreover, crosslinking allows regulation of the nanocarriers pore size, degradation rate, and mechanical strength, balancing stability and biocompatibility (Wang et al., 2022a).

Graft copolymerization for nanocarrier preparation involves synthesizing amphiphilic or functionalized copolymers through covalent grafting reactions between main-chain and branch monomers, which then self-assemble into nanostructures. Grafting rate and monomer ratio directly determine the amphiphilic balance of copolymers: an excessive grafting rate enhances hydrophobicity, leading to particle aggregation, while an insufficient grafting rate impedes the formation of stable core-shell structures. The polarity of the reaction solvent affects monomer solubility and reactivity polar solvents facilitate the formation of small-sized micelles, whereas non-polar solvents typically yield increased particle sizes with broader size distributions. Initiator concentration modulates the polymerization rate, thereby influencing the molecular weight distribution of the copolymer, which in turn governs the morphological regularity of micelles and their drug-loading stability. This approach can form core-shell micelles with a particle size of 80–150 nm in aqueous media. The hydrophobic core achieves an encapsulation efficiency of 80%–95% for lipid-soluble drugs, while the hydrophilic polysaccharide chains on the shell show significantly reduced carrier cytotoxicity (Verma et al., 2023).

Enzyme-catalyzed specific degradation and modification form the core of nanocarrier preparation, providing both environment-friendly manufacturing and high selectivity. Enzyme type determines degradation sites and product structure: α-amylase primarily hydrolyzes α-1,4 glycosidic bonds in starch, yielding short-chain fragments, whereas glucoamylase can further cleave α-1,6 glycosidic bonds to produce products with enhanced crystallinity. Enzyme concentration, reaction pH, and temperature must align with the enzyme’s optimal activity conditions—excessive concentration readily leads to over-degradation, while pH deviation from the optimum diminishes enzymatic activity, thereby compromising particle size uniformity. Substrate concentration (e.g., starch milk concentration) affects both reaction efficiency and product morphology: low concentrations favor spherical particle formation, whereas high concentrations may result in rod-like or aggregated structures. Enzymatic hydrolysis is the most mature method for starch nanoparticle preparation: α-amylase hydrolyzes starch milk to remove amorphous regions, which is followed by low-temperature retrogradation to form crystalline nanoparticles (Sun et al., 2023).

The composite ratio is a critical determinant of carrier morphology and performance: at polysaccharide-to-inorganic mass ratios of 2:1∼5:1, core-shell or encapsulation structures are readily formed, whereas imbalanced ratios may induce component segregation or aggregation (Li, 2023). The compositing method influences intercomponent binding strength, for instance, in situ synthesis enables uniform dispersion of inorganic components within the polysaccharide matrix, thereby enhancing carrier stability and functional synergy, while physical mixing, though operationally facile, is prone to phase separation. The size and surface properties of functional components affect the dispersibility, targeting efficiency, and stimuli-responsive sensitivity of composite carriers; for example, nanoscale inorganic particles can augment photothermal and chemodynamic performance, whereas positively charged lipid components improve carrier-cell membrane interactions (Zhang et al., 2023). Polysaccharides possess natural biological activities such as anti-inflammatory and immunomodulatory effects, but nanocarriers constructed from a single polysaccharide often show defects such as insufficient stability and poor targeting (An, 2022). In contrast, composite carrier materials not only exhibit good biocompatibility and targeted recognition capabilities but also precisely compensate for the performance shortcomings of polysaccharide carriers. After composite construction, the two components exert a synergistic effect: they fully retain their respective biological activities while significantly improving the carrier’s loading efficiency, sustained-release performance, and in vivo targeted-delivery capacity (Ma et al., 2024). These effects greatly enhance the disease-intervention activity, providing an efficient solution in areas such as precise drug delivery. In summary, the preparation methods of polysaccharide nanocarriers have formed four core systems: physical recombination, chemical modification, biological regulation, and composite construction. Each technical route exhibits specific advantages focused on structure, performance, and application. The major advantages and disadvantages of the polysaccharide nanocarriers preparation methods are presented in Table 1.

From the perspective of development trends, future studies on polysaccharide nanocarrier preparation technologies will focus on improving their precision and environmental friendliness. With the development of enzyme engineering and synthetic biology, the preparation efficiency and product controllability of biological methods can be further improved by modifying the catalytic efficiency and specificity of enzymes. Moreover, the composite construction strategy can meet the needs of precise drug delivery by yielding polysaccharide composite carriers with targeted recognition, pH- and temperature-responsive release, and bioimaging functions. Simultaneously, effort to improve the environmental friendliness of these methods should not be limited to reagent selection, but should extend to the entire process, yielding processes that reduce solvent consumption and improve process stability. In addition, most current technologies are in the laboratory stage. Future studies should aim to strengthen the link from laboratory research to pilot-scale amplification and finally to industrial production. By optimizing preparation equipment and process parameters, solving the issues of uniformity, cost, and quality control in large-scale production, polysaccharide nanocarriers can progress from basic research to clinical application.

2.3 Characterization and detection techniques of polysaccharide nanocarriers

Common morphologies of polysaccharide nanocarriers primarily include nanospheres, nanocapsules, and nanofibers, each exhibiting distinct compatibilities between structural features and application scenarios (detailed characteristics and applicable contexts are illustrated in the Table 2). Given significant disparities in structural attributes and functional orientations among these carriers, establishing a systematic characterization framework is imperative for precisely matching application requirements and elucidating core performance metrics.The characterization of polysaccharide nanocarriers is based on a four-dimensional evaluation system that encompasses physicochemical properties, structural characteristics, drug-loading performance, and biocompatibility. Comprehensive analysis from macroscopic performance characteristics to microscopic mechanistic assessments is achieved through combinations of multiple techniques, and the precise determination of key indicators needs to be strengthened in combination with application scenarios.

TABLE 2

Shapes of structures	Figure	Application
Nanospheres		Encapsulation of chemotherapeutic agents, proteins, peptides, or gene-based therapeutics Surface functionalization with fluorescent dyes or magnetic resonance imaging contrast agents for in vivo imaging and disease diagnosis Surface immobilization of antibodies or enzymes for detecting biomarkers such as tumor markers
Nanocapsules		Drug delivery: Encapsulation of chemotherapeutic agents, antibiotics, or gene-based drugs to improve stability and bioavailability. Vaccine delivery: Encapsulation of antigens or adjuvants for mucosal or injectable administration to enhance immune responses. Cosmetics and food: Encapsulation of vitamins, antioxidants, or flavor compounds to prolong shelf life and enable controlled release of active ingredients
Nanofibers		Mimicking extracellular matrix (ECM) structure for regeneration of skin, bone, cartilage, or neural tissue. Drug loading within fiber interiors or on surfaces, controlling release rates through diffusion or erosion to prolong therapeutic duration. Biosensors and filtration: Detection of gases, liquids, or biomolecules, or serving as high-efficiency filtration materials

Common morphologies and applications of polysaccharide nanocarriers.

2.3.1 Detection of physicochemical properties

The characterization of physicochemical properties focuses on particle-size distribution and zeta potential. Dynamic light scattering (DLS), which is based on the principle of Brownian motion, has become the gold standard method for particle-size detection. During detection, the refractive index and temperature of the dispersion medium have to be controlled; the average particle size is calculated by cumulative analysis; and the polydispersity index (PDI) is obtained. The number distribution is verified by Malvern NanoSight Tracking Analyzer to avoid detection deviations caused by a few large particles, and zeta potential detection is directly related to carrier stability and cell interactions (Zhong et al., 2022).

2.3.2 Detection of structural characteristics

The characterization of structural characteristics is based on the complementary application of microscopic imaging and spectroscopic techniques. In morphological assessments, scanning electron microscopy (SEM) can clearly show the spherical morphology and surface smoothness of chitosan nanoparticles, while transmission electron microscopy (TEM) can intuitively reveal the core-shell structure of dextran-based nanomicelles. Cryogenic electron microscopy (Cryo-EM) can analyze the three-dimensional structure of carriers in a near physiological state without staining; for example, Cryo-EM can reveal the porous channel distribution of starch-based stimulus responsive carriers, providing direct evidence for studies of drug-release mechanisms (Tan et al., 2020). Atomic force microscopy (AFM) can yield surface roughness data through probe scanning. The roughness (Ra) of food-grade carriers needs to be <5 nm to reduce oral irritation. In crystal structure analysis, X-ray diffraction (XRD) can distinguish the crystal type of nanoparticles. Verification of chemical structure is mainly based on Fourier transform infrared spectroscopy (FT-IR) (Ye et al., 2023).

2.3.3 Detection of drug loading performance

Assessments of drug-loading performance should aim to accurately quantify the loading efficiency and release behavior. Measurements of encapsulation efficiency (EE) and drug loading (DL) should focus on selecting separation methods compatible with the drug properties: small-molecule hydrophobic drugs can be detected using ultraviolet visible spectrophotometry (UV-Vis), while water-soluble drugs should be separated by a combination of dialysis and high-performance liquid chromatography (HPLC) (Al-Nakashli et al., 2023). The encapsulation integrity of nucleic acid drugs should be verified using gel electrophoresis retardation assay. Studies of in vitro release behavior should employ a simulated physiological environment; specifically, assessments of oral carriers should adopt a two-step release approach using pH 1.2 hydrochloric acid solution and pH 7.4 phosphate buffer (Espinoza et al., 2023).

2.3.4 Detection of biocompatibility

Characterizations of biocompatibility cover both cellular and in vivo levels and directly influence the feasibility of using the carrier. Cytotoxicity evaluations are based on the cell counting kit (CCK)-8 method to detect the survival rate of human cells: the cell survival rate of food-grade carriers should be ≥90%, while the survival rate of drug-delivery carriers should be >80% at an appropriate concentration. Cell staining can intuitively reveal cell morphology, avoiding the limitations of single proliferation rate detection. Blood compatibility should be verified by hemolysis test: a hemolysis rate <5% at a carrier concentration of 5 mg/mL is considered appropriate (Yao et al., 2024).

In summary, the characterization of polysaccharide nanocarriers is a four-dimensional evaluation system centered on physicochemical properties, structural characteristics, drug-loading performance, and biocompatibility. Through the combination of multiple technologies, comprehensive analysis of characteristics ranging from macroscopic particle-size distribution and microscopic core-shell structure to in vivo targeted distribution can be realized. Simultaneously, differentiated index thresholds have been established for different application scenarios such as delivery of food-grade materials and drugs. This scenario-based characterization serves as a key basis for carrier function adaptation.

From the perspective of technical applications, this system can effectively solve the basic evaluation issues in carrier research and development. For example, Cryo-EM can reveal the three-dimensional structure in a near physiological state, and gel electrophoresis can verify the encapsulation integrity of nucleic acid drugs, significantly improving the reliability of results. However, some bottlenecks remain unresolved: For one, the correlations between data obtained using different technologies have to be strengthened. The deviations between the average particle sizes measured by DLS and the actual size observed by TEM represent one such example, since uniform calibration standards to reconcile these deviations are currently lacking. Moreover, the existing techniques show insufficient ability to achieve dynamic characterization in complex biological environments. Although the existing in vitro release simulation methods can reproduce the gastrointestinal pH conditions, they cannot simulate dynamic processes such as blood flow and cell phagocytosis in vivo, limiting the correlation between some in vitro results and in vivo effects.

From the perspective of development trends, polysaccharide nanocarriers exhibit core characteristics compatible with clinical applications in the biomedical arena: their colloidal stability is ensured through steric hindrance and hydration layers formed by hydrophilic polysaccharide chains, maintaining uniform dispersion under physiological pH, acidic tumor microenvironment conditions, and gastrointestinal pH fluctuations (absolute zeta potential ≥30 mV, PDI <0.3), thereby preventing in vivo aggregation, prolonging circulation half-life, and tolerating digestive enzymes and serum proteins to meet diverse administration route requirements. Drug loading capabilities demonstrate both broad-spectrum applicability and precision, efficiently encapsulating lipophilic/hydrophilic small-molecule drugs and biomacromolecules (e.g., nucleic acids, peptides) via hydrophobic interactions, hydrogen bonding, or ionic bonding, achieving encapsulation efficiencies of 80%∼95% and maximum drug loading of 35%. Moreover, stimuli-responsive sustained release can be realized through high GSH levels, acidic pH, or specific enzymes in the tumor microenvironment (release period 72∼120 h), protecting drugs from degradation while enhancing lesion site concentrations. Biocompatibility extends across cellular, hematological, and systemic metabolic levels, exhibiting ≥90% cell viability at concentrations ≤100 μg/mL in normal cells, <2% hemolysis rate at 5 mg/mL for intravenous injection, no platelet aggregation or organ accumulation risk, with degradation products capable of participating in metabolic cycles. More importantly, certain natural polysaccharides inherently possess immunoadjuvant activity, capable of stimulating dendritic cell maturation and promoting cytokine secretion through regulation of molecular weight and surface modification degree, thereby achieving synergistic effects when combined with targeting modifications or immunotherapeutic agents, providing safe and efficient carrier support for precision disease therapy.

Regarding development trends, characterization techniques for polysaccharide nanocarriers require refined improvements toward precision, dynamism, and intelligence. Precision techniques (e.g., combined atomic force microscopy and Raman spectroscopy) deepen structure-performance correlative analysis; dynamic methods (e.g., combined fluorescent probes and magnetic resonance imaging) enable real-time tracking of in vivo degradation, drug release, and distribution dynamics; intelligent algorithms facilitate rapid screening of optimal preparation parameters, while coordinated safety-function evaluation (e.g., metabolomics-based long-term safety assessment) prevents performance imbalance from single-index optimization. The integration of these core characteristics with advanced characterization technologies not only provides a solid foundation for optimized carrier design but also drives the in-depth exploration of their inherent biomedical activity potential.

2.4 Limitations of polysaccharide nanocarriers

Despite the significant advantages of natural polysaccharide-based nanocarriers in disease treatment including biocompatibility, biodegradability, and targeted delivery. Their development currently faces numerous pressing limitations. The physicochemical properties of polysaccharides exhibit inherent variability, as parameters such as molecular weight, degree of branching, and solubility are susceptible to variations in source, extraction, and purification processes (Kotenkova et al., 2025). This variability not only increases the difficulty in achieving reproducibility and scalable production of nanoformulations, making it challenging to meet the standardization requirements for clinical applications, but also poses challenges in regulating the balance between drug loading and controlled release (Sun L. et al., 2025). For hydrophobic drugs in particular, polysaccharide carriers demonstrate limited loading efficiency and difficulty in precisely achieving on-demand drug release at target sites, often resulting in initial burst release or release kinetics that do not match disease progression. This mismatch between drug loading and controlled release reduces therapeutic efficacy, causes premature drug leakage in non-targeted sites, and triggers unexpected toxicity risks. Additionally, some polysaccharides may interact unexpectedly with the host immune system, inducing immunogenic reactions or local inflammation, which further compromises their biocompatibility (Li et al., 2025b). These challenges related to in vivo stability and biocompatibility subject polysaccharide-based nanocarriers to stringent regulatory approval thresholds during clinical translation, as their biosafety evaluation, in vivo pharmacokinetic characterization, and long-term toxicity data remain to be systematically established. Furthermore, the complex preparation and modification processes result in high production costs, which further limit their transition from laboratory research to clinical application. The targeted delivery capability of polysaccharide-based nanocarriers is also insufficient, as existing targeting ligand modification strategies often suffer from inadequate targeting efficiency and vulnerability to clearance by biological barriers, making it difficult to achieve high-efficiency drug accumulation at lesion sites. These combined limitations constitute major obstacles to the widespread clinical application of polysaccharide-based nanocarriers, which need to be progressively overcome through material modification, process optimization, and interdisciplinary collaboration (Kumar et al., 2025).

Natural polysaccharide-based nanocarriers, despite their notable advantages in biocompatibility, biodegradability, and targeted delivery, face fundamental obstacles in clinical translation that severely constrain practical applications. Primarily, inherent variability in polysaccharide physicochemical properties—stemming from diverse sources, extraction, and purification protocols—results in inconsistent key parameters (molecular weight, branching degree, solubility). This variability not only undermines nanoformulation reproducibility and scalable manufacturing, failing to meet stringent clinical standardization criteria, but also impedes precise tuning of the drug loading–controlled release balance. Particularly for hydrophobic therapeutics, polysaccharide carriers show limited loading efficacy and poor on-demand release at target sites, frequently causing initial burst release or mismatched release kinetics relative to disease progression, thereby compromising therapeutic outcomes and posing toxicity risks through off-target drug leakage. Furthermore, certain polysaccharides may engage in unintended immune interactions, provoking immunogenic reactions or local inflammation, while systematic biosafety assessment, in vivo pharmacokinetic profiling, and long-term toxicity data remain inadequately established, creating substantial regulatory hurdles for clinical approval. Additionally, existing targeting ligand modification strategies exhibit insufficient targeting efficiency, with carriers prone to clearance by biological barriers, thus precluding effective drug accumulation at lesion sites. Ultimately, complex preparation and modification procedures drive prohibitively high production costs, further impeding the transition from bench to bedside.

3 Bioactivities of polysaccharide nanocarriers

The bioactivities of polysaccharide nanocarriers can be attributed to the inherent biological properties of natural polysaccharide molecules as well as the synergistic enhancement effects conferred by the nanoscale level. The chemical structures of many natural polysaccharides are similar to some components in the human body, allowing their safe recognition and acceptance by organisms and eventually facilitating their enzymatic degradation into non-toxic monosaccharides for metabolism and excretion. These factors fundamentally avoid the toxic adverse reactions associated with synthetic materials (Li et al., 2023). Second, the specific polysaccharides themselves possess defined pharmacological activities. For instance, chitosan exhibits antibacterial and wound-healing capabilities owing to its positive charge; hyaluronic acid can target cancer cells and repair tissues; and sulfated dextran demonstrates anticoagulant activity (Ruan et al., 2023). Figure 4 systematically presents the five core bioactivities and molecular mechanisms of polysaccharide nanocarriers: antitumor, immunomodulatory, antioxidant, anti-inflammatory, and neuroprotective activities. For antitumor activity, HA’s CD44 receptor targeting and chitosan’s EPR effect combined with magnetic field guidance lead to drug enrichment at tumor sites, overcoming multidrug resistance and reducing off-target toxicity, as evidenced by reduced IC50 values of HA-AXT-M nanomicelles. The immunomodulatory mechanism activates dendritic cells (DCs), promotes macrophage polarization, and enhances the immunogenicity and targeting of immunotherapeutic agents, exemplified by Dex-NB-CPT nanosystems inducing immunogenic cell death. Antioxidant activity utilizes -COOH and -OH groups to scavenge free radicals, protecting oxidation-sensitive drugs and adapting to oxidative stress microenvironments, as demonstrated by the extended drug half-life of double-grafted dextran nanomicelles. The anti-inflammatory effect blocks the NF-κB pathway, achieving targeted enrichment at inflammatory sites with reduced drug dosage and improved tolerability, illustrated by CS-CUR nanoparticles inhibiting pro-inflammatory cytokine secretion. Neuroprotective activity promotes microglial M2 polarization, enabling blood-brain barrier penetration and ameliorating neuroinflammatory microenvironments for delivery to central nervous system diseases, as confirmed by the effects of FDCDs nanoparticles in Parkinson’s disease models. More importantly, the nanostructure imparts a unique “enhancement” mechanism: the immense specific surface area and the enhanced permeability and retention (EPR) effect improve drug accumulation at the disease site. By simultaneously functioning as a “protective compartment” and “transport vehicle,” the nanocarrier shields active ingredients from degradation and achieves more precise cellular delivery through targeting modifications (Ma et al., 2025). Consequently, the intrinsic bioactivity of the polysaccharide is synergistically amplified with the therapeutic efficacy of the loaded drug, yielding collaboratively enhanced treatment outcomes. Therefore, the bioactivity of polysaccharide nanocarriers represents the perfect integration of their natural intrinsic activity and the enhancing capabilities of nanotechnology.

FIGURE 4

3.1 Antitumor activity

Cancer multidrug resistance (MDR) represents a critical bottleneck limiting chemotherapy efficacy. Its mechanisms are complex and multifaceted, primarily including drug efflux due to overexpression of ATP-binding transporter proteins, reduced drug uptake by tumor cells, enhanced DNA repair capacity, dysregulated apoptotic pathways, and the hypoxic and acidic characteristics of the tumor microenvironment. These factors interact synergistically, leading to insufficient intracellular drug concentrations and treatment failure in over 90% of advanced cancer patients. Traditional strategies to overcome MDR suffer from poor specificity, low bioavailability, severe off-target toxicity, and complex pharmacokinetic interactions. Polysaccharide-based nanocarriers can effectively circumvent MDR; the specific anti-tumor mechanisms are illustrated in Figure 5. There is an urgent need to develop novel carrier systems integrating targeted delivery, synergistic efficacy, and biosafety (Duan et al., 2023).

FIGURE 5

Li et al., 2025b).

The anti-tumor activity of polysaccharide nanocarriers is achieved through mechanisms including targeted delivery, immunomodulation, direct tumor cell killing, and inhibition of angiogenesis, thereby effectively circumventing the development of cancer multidrug resistance (Wang X. et al., 2025).

Hyaluronic acid enables active targeting by binding to the CD44 receptor, which is highly expressed on the surface of tumor cells. Hyaluronic acid-functionalized axitinib nanomicelles (HA-AXT-M) have shown an EE of 87.92% for axitinib. Subsequent in vitro experiments revealed that HA-AXT-M can be efficiently internalized by MCF-7 breast cancer cells through CD44-mediated endocytosis, with the half-maximal inhibitory concentration (IC50) of these nanomicelles being significantly lower than those of unmodified micelles and the free drug (Mugundhan and Mohan, 2025).

Chitosan-based nanocomposites can be compounded with magnetic nanoparticles, carbon nanotubes, etc. Subsequently, these nanocomposites can achieve passive accumulation at tumor sites through the EPR effect and active targeting guided by an external magnetic field, yielding a higher inhibition rate in comparison with free drugs against solid tumors such as glioma and liver cancer (Khorasani and Naghib, 2025). Furthermore, chitosan composite carriers can downregulate the expression of molecules such as matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF)-C, reduce the migration of breast cancer cells, and decrease the wound-healing rate by 60%, thereby further inhibiting tumor progression (Zhang J. M. S. et al., 2025).

Polysaccharide-based nano-selenium has shown remarkable efficacy in directly killing tumor cells. Astragalus polysaccharide-modified nano-selenium can downregulate Bcl-2 expression, upregulate Bax protein expression, and activate the caspase-3/9 pathway, leading to an apoptosis rate of 45.6% in HepG2 liver cancer cells (Jiao et al., 2022). Chestnut polysaccharide-nano-selenium has been shown to arrest the cell cycle of HeLa cervical cancer cells at the G2/M phase, downregulate cyclin B1 expression by 40%, and significantly inhibit cell proliferation (Wang et al., 2022b). Kelp polysaccharide-nano-selenium inhibits the lysosomal function of human HepG2 liver cancer cells to block the late stage of autophagy, resulting in the accumulation of damaged organelles and enhanced apoptosis (Cui et al., 2019). Lentinan and folic acid self-assembled nanoparticles can activate bone marrow-derived dendritic cells (DCs), increasing the expression of CD80 and CD86 on their surfaces to 35.8% and 25.7%, respectively, and thereby activating cytotoxic T lymphocytes (Zeng et al., 2019). Additionally, Schisandra polysaccharide drug-loaded nanoparticles can downregulate the VEGF expression level in renal cancer cells by 58%, reduce the expression of CD31 and CD34 in tumor tissues, and decrease the microvessel density by 42% (Wang C. L. et al., 2025). Astragalus polysaccharide and curcumin composite nanoparticles can also improve tumor vascular morphology, reduce blood vessel branches by 30%, enhance vascular wall integrity, and block tumor nutrient supply through vascular regulation (Li et al., 2022).

3.2 Immunomodulatory activity

The immunomodulatory activity of polysaccharide-based nanocarriers represents one of their core advantages distinguishing them from traditional nanocarriers. This activity originates from the synergistic enhancement between the intrinsic biological properties of natural polysaccharides and the nanostructural design (Yanqing, 2024). Natural polysaccharides (e.g., hyaluronic acid, chitosan, dextran) can serve as immunoadjuvants per se by binding to pattern recognition receptors (e.g., TLR, CD44) on immune cell surfaces to initiate innate immune responses. Nanoscale modification not only enhances the bioavailability and targeting capability of polysaccharides but also optimizes immune cell recognition and uptake efficiency by modulating carrier morphology, particle size, and surface charge. Such carriers can effectively activate DC maturation, promoting secretion of pro-inflammatory cytokines such as IL-6 and TNF-α, while inducing macrophage polarization toward the M1 phenotype to enhance anti-tumor immune surveillance (Ma et al., 2024). Moreover, they trigger tumor cell immunogenic cell death (ICD) through synergistic effects of chemodynamic therapy (CDT), photothermal therapy (PTT), etc., releasing “danger signals” such as high-mobility group box 1 (HMGB-1) and calreticulin (CRT), which further recruit and activate T lymphocytes to potentiate adaptive immune responses. The specific process is illustrated in the Figure 6.

FIGURE 6

Xia et al., 2025).

In terms of immune activation, functional modification of polysaccharides can substantially enhance their targeted-activation ability on immune cells such as macrophages. AAP-SH-AuNPs, which are constructed by combining thiol-modified fructan (AAP70–1) with gold nanoparticles, can activate macrophages through the TLR4/MyD88/NF-κB signaling pathway, and their macrophage-activation ability is 1.45 times higher than that of free fructan. These nanoparticles can remarkably improve macrophage phagocytic activity, promote ROS production, and upregulate the secretion of pro-inflammatory factors such as IL-6, IL-1β, and TNF-α. In a chloramphenicol-induced zebrafish immunosuppression model, this complex effectively restored the numbers of macrophages and neutrophils, increased the levels of nitric oxide and ROS, and reversed the immunosuppressive state (Wang T. L. et al., 2025). Similarly, the Dex-NB-CPT nanosystem, which is constructed by loading camptothecin onto dextran through a photoresponsive linker, can precisely release drugs under 366-nm light irradiation, inducing immunogenic cell death (ICD) of tumor cells. This nanosystem can promote calreticulin exposure and the release of high-mobility group box 1 protein (HMGB1), thereby activating the polarization of macrophages toward the M1 phenotype and promoting dendritic cell maturation, laying the foundation for subsequent adaptive immune responses (Xu et al., 2025).

3.3 Anti-inflammatory activity

The anti-inflammatory activity of polysaccharide nanocarriers can be attributed to the synergistic interactions between the inherent biological activity of polysaccharides and their nanostructures. When loaded with conventional anti-inflammatory drugs, polysaccharide nanocarriers allow targeted drug delivery and exert synergistic effects with the drugs through their intrinsic anti-inflammatory activity. This dual-effect characteristic of integrating carrier functions and drug efficacy can serve as a novel strategy for the treatment of chronic inflammatory diseases (Liu et al., 2025).

For cellular targeting and functional regulation, polysaccharide nanocarriers can achieve precise regulation of specific inflammatory sites through ligand modification or inherent biological activity. Chitosan-epigallocatechin-3-gallate (EGCG)-hyaluronic acid nanoparticles can specifically bind to the CD44 receptor, which is overexpressed on inflamed colonic epithelial cells, to allow targeted delivery of EGCG to lesion sites and significantly inhibit the excessive activation of macrophages. In the dextran sodium sulfate (DSS)-induced ulcerative colitis mouse model, these nanoparticles reduced the expression of inducible nitric oxide synthase (iNOS) in pro-inflammatory M1 macrophages in colonic tissues, promoted the polarization of anti-inflammatory M2 macrophages, and improved the maturation efficiency of dendritic cells (DCs), thereby indirectly enhancing T cell-mediated adaptive immunity (Li, 2023). Similarly, a curcumin-loaded nanosystem based on yeast glucan (GP) can be recognized by macrophages through the Dectin-1 receptor. In the acute intestinal inflammation model, this nanosystem reduced the secretion of IL-1β and TNF-α by macrophages and promoted the conversion of macrophages to the M2 phenotype, alleviating intestinal immune disorders by upregulating IL-10 expression (Li et al., 2022).

In terms of cytokine balance regulation, polysaccharide nanocarriers can bidirectionally regulate the levels of pro-inflammatory and anti-inflammatory factors to restore immune homeostasis. Through the synergistic effects of selenium, GP-selenium nanoparticles have been shown to promote the secretion of cytokines such as IL-2 by immune cells to secrete and enhance T cell proliferation capacity. In in vitro experiments, the proliferation rate of CD4⁺ T cells induced by GP-selenium nanoparticles was 25% higher than that induced by pure GPs. Additionally, these nanoparticles can activate the cytotoxicity of natural killer (NK) cells and improve the clearance efficiency of abnormal cells (Sun J. et al., 2025).

The regulation of key signaling pathways is one of the core mechanisms by which polysaccharide nanocarriers exert immunomodulatory effects. Polysaccharide nanocarriers can inhibit excessive immune activation by interfering with pathways such as the NF-κB, mitogen-activated protein kinase (MAPK), and NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) pathways. For example, chitosan-curcumin nanoparticles (CS-CUR) can reduce the nuclear expression of NF-κB by inhibiting IκB phosphorylation. In a lipopolysaccharide (LPS)-induced BV-2 microglia model, these nanoparticles reduced the nuclear expression of NF-κB p65 by 60%, inhibiting the transcription of IL-6 and TNF-α (Lopes et al., 2021). Polysaccharide nano-selenium (P-SeNPs) have been shown to regulate the MAPK pathway to reduce the phosphorylation levels of p38 and JNK, inhibit microglial activation in the neuroinflammation model, and reduce the release of pro-inflammatory factors (Liu et al., 2025). Regarding the NLRP3 inflammasome, Ganoderma lucidum polysaccharide-curcumin nanoparticles can inhibit the assembly of NLRP3 and apoptosis-associated speck-like protein (ASC) by scavenging ROS, reducing caspase-1 activity by 58% and thereby decreasing the maturation and secretion of IL-1β and alleviating neuroimmune disorders (Singh et al., 2021).

3.4 Antioxidant activity

Polysaccharide nanocarriers can achieve neuroprotection-related immunomodulation by regulating the core components of the neuroimmune microenvironment (such as microglia and astrocytes), intervening in key inflammatory signaling pathways, and balancing inflammatory factors (Cao et al., 2024).

When polysaccharides are converted into nanocarriers, their antioxidant activity is substantially enhanced. The nanostructure endows the carrier with a higher specific surface area and dispersibility, which increases the contact efficiency between the carrier and free radicals and allows the carrier to serve as a vehicle for loading antioxidant active ingredients like selenium and quercetin, reducing the degradation and loss of these active components in vivo and improving cellular uptake efficiency (He et al., 2023).

Through synergistic effects with the loaded components, polysaccharides can achieve superior antioxidant effects in comparison to those shown by polysaccharides alone. In one study, researchers used Acanthopanax senticosus polysaccharide as the raw material to construct two types of antioxidant nanocarriers. At the same concentration, the DPPH and ABTS scavenging rates of both were significantly higher than those of the plain A. senticosus polysaccharide. In vivo experiments further confirmed that selenium-ASPS could increase the activity levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in the serum, heart, liver, spleen, and kidney tissues of mice with d-galactose-induced oxidative damage, reduce malondialdehyde (MDA) and aspartate transferase (AST)/alanine aminotransferase (ALT) levels, and repair liver cell swelling and necrosis. The mechanism underlying these effects is closely related to the activation of the terminal carbon-hydrogen atoms of the polysaccharide molecules by selenium and the enhanced efficiency attributable to the nanostructure (Li, 2023). Chitosan-based nanocarriers can achieve enhanced antioxidant activity through single carrier design or composite system construction. Single-chitosan nanoparticles prepared by ionic gelation method, when loaded with resveratrol, showed slow release in simulated gastrointestinal fluid and significantly higher DPPH radical-scavenging rate within 24 h in comparison with the free drug. A nanoparticle composite with sodium alginate, when loaded with quercetin, showed significantly improved ABTS radical-scavenging rate, could reduce ROS levels in LPS-induced RAW264.7 cells, while chitosan inhibited NF-κB pathway activation (Youssef et al., 2025). Chitosan-selenium nanocomposites can reduce the agglomeration of nano-selenium, remain stable at 4 °C for 35 days, and show significantly improved OH radical-scavenging rate in comparison with bare nano-selenium (Yang et al., 2023). Carrier composites with hyaluronic acid can penetrate the blood–brain barrier; composites loaded with chondroitin sulfate have shown the ability to reduce ROS levels in the brain of Alzheimer’s disease model mice and protect nerve cells from hydrogen peroxide damage (Yan et al., 2024). Double-grafted dextran nanomicelles achieved optimized antioxidant performance through structural modification. The nanomicelles formed by ultrasonic self-assembly and loaded with quercetin showed better free radical-scavenging rates than free quercetin, and the scavenging rate remained basically unchanged after 8 h, while that of free quercetin decreased significantly. For LPS-induced RAW264.7 cells, these nanomicelles significantly reduced ROS levels, upregulated antioxidant protein expression by activating the Nrf2 pathway, and strengthened the cellular antioxidant capacity (He et al., 2023).

3.5 Neuroprotective activity

By leveraging the biocompatibility of natural polysaccharides and the targeted-delivery advantages of nanostructures, polysaccharide nanocarriers can achieve neuroprotective immunomodulation by regulating the core components of the neuroimmune microenvironment, intervening in key inflammatory signaling pathways, and balancing the expression of inflammatory factors. The use of these nanocarriers can provide new strategies for interventions targeting the immune-related neural damage in Alzheimer’s disease, Parkinson disease, and ischemic stroke. The related mechanisms and experimental evidence have been confirmed by numerous studies (Liu et al., 2025).

From the perspective of regulating neuroimmune cell function, polysaccharide nanocarriers can precisely regulate microglial polarization and astrocyte activation, improving the neuroinflammatory microenvironment. For example, the use of fucoidan nanoparticles (FDCDs) in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model has been shown to inhibit the overexpression of glial fibrillary acidic protein (GFAP) in astrocytes through the TLR4/NF-κB pathway, reduce glial scar formation, and increase IL-10 levels (P < 0.01), alleviating neuroimmune injury (Tziveleka et al., 2025). Interventions in key signaling pathways form the core mechanism by which polysaccharide nanocarriers regulate neuroimmunity. An ROS-responsive nanocarrier constructed from sulfated chitosan in an ischemic stroke model could release SCS and rapamycin through boronic ester bond cleavage, inhibiting NF-κB p65 nuclear translocation and p38 MAPK phosphorylation. In a mouse transient middle cerebral artery occlusion (tMCAO) model, administration of this nanocarrier reduced the level of the pro-inflammatory factor IL-6 in the infarct area, promoted the expression of the anti-inflammatory factor IL-10, and protected the blood–brain barrier by regulating microglial M2 polarization (Cao et al., 2024).

In disease-specific immunomodulation for neurodegenerative diseases, polysaccharide nanocarriers demonstrate disease adaptability. For AD, fucoidan-chitosan composite nanoparticles can mitigate amyloid beta (Aβ)-induced overactivation of microglia. In an APP/PS1 mouse model, they reduced brain infiltration of IBA1+ microglia, inhibited NLRP3 inflammasome activation, and reduced Aβ deposition-related neuroinflammation (Tziveleka et al., 2025). For PD, polysaccharide nano-selenium (P-SeNPs) can modulate the gut microbiota through the “gut-brain axis,” increase the abundance of Bifidobacterium, and reduce endotoxin entry into the bloodstream, thereby inhibiting central microglial activation and reducing the loss of dopaminergic neurons in the substantia nigra of MPTP model mice by 50% (Liu et al., 2025).

4 Conclusions and future perspectives

This review systematically examined the current research landscape of polysaccharide nanocarriers. From the perspective of core materials, it delineated the structural characteristics and functional advantages of major types of polysaccharide nanocarriers, including those based on chitosan, hyaluronic acid, dextran, fructan, starch, and TCM polysaccharides; these advantages included the cationic mucoadhesive properties of chitosan, the CD44 receptor-targeting ability of hyaluronic acid, and the synergistic bioactivity of TCM polysaccharides. The integration of these natural polysaccharides with nanotechnology not only addresses the limitations of traditional polysaccharides, such as poor solubility, inadequate stability, and weak targeting capability, but also endows these carriers with nanoscale advantages, including high drug EE, responsive drug release, and integrated “diagnosis-treatment-monitoring” (theranostic) capabilities. From the perspective of bioactivity, thus review elucidates how polysaccharide nanocarriers, through four core mechanisms (immunomodulation, antioxidant and anti-inflammatory effects, neuroprotection, and antitumor activity), demonstrate substantial potential for targeted interventions in complex diseases such as neurodegenerative disorders, cancers, and inflammatory diseases, providing innovative strategies for treatment across multiple fields.

Although polysaccharide nanocarriers have demonstrated considerable application value, the existing research on these nanocarriers encounters unresolved challenges. First, most of the existing studies have focused on single polysaccharides or single diseases. Consequently, systematic analyzes of the relationships among polysaccharide structure, carrier function, and disease suitability are lacking. Future studies should aim to deepen research on structure-activity relationships to establish a unified theoretical framework and application strategy for guiding the precise design of carriers. Second, the clinical application of these nanocarriers faces bottlenecks such as the complexity of scalable production processes, insufficient in vivo circulation stability, and a lack of long-term safety data. Thus, establishment of green and efficient preparation techniques, optimization of the in vivo pharmacokinetic properties of carriers, and validation of their safety and efficacy through long-term animal studies and early-stage clinical research are essential. Third, multifunctional integration and precise targeting by these nanocarriers show room for improvement. Further exploration of multi-ligand modifications, co-delivery of multiple cargoes, and intelligent responsiveness (e.g., multi-stimuli-responsive drug release) could enable dynamic disease monitoring and precise interventions. Fourth, the interdisciplinary application scenarios of these nanocarriers need expansion. By integrating requirements from nutrition science and biomedicine, polysaccharide nanocarriers showing combined therapeutic and nutritional functions could be developed, such as functional food additives for adjuvant therapy in neurodegenerative diseases or nutritional delivery systems for postoperative recovery in patients with cancer.

Currently, polysaccharide nanocarriers demonstrate remarkable application potential in the pharmaceutical field. However, their translation from laboratory research to industrial manufacturing and clinical implementation still faces numerous critical challenges. At the synthesis level, conventional methods such as emulsion crosslinking and ionic gelation suffer from insufficient sophistication and controllability, and the difficulty in precisely regulating polysaccharide structures results in low drug encapsulation efficiency and loading capacity, as well as poorly controlled release kinetics. In terms of scale-up production, the high costs of raw material extraction and purification, coupled with substantial capital investment for equipment upgrading, lead to widened particle size distributions, decreased encapsulation efficiency, and significant batch-to-batch variations during process scale-up. Additionally, immature quality control systems and ambiguous pharmaceutical regulatory standards further impede their industrialization. Regarding performance efficacy and biosafety, discrepancies between in vitro and in vivo environments result in actual therapeutic outcomes below expectations, necessitating improvements in targeting capability and stability. Potential risks including crosslinker residues, immunogenicity, and long-term toxicity remain incompletely resolved, while stringent storage requirements increase logistical costs. Moving forward, breakthroughs in continuous manufacturing technology innovation, development of novel polysaccharide materials, optimization of scale-up strategies, and in-depth investigation of surface modification and in vivo behavior are required to overcome these translational bottlenecks, thereby facilitating the substantive application of polysaccharide nanocarriers in the modernization of traditional Chinese medicine and precision medicine.

In the future, with deeper integration of materials science, medicine, nutrition, and other disciplines, polysaccharide nanocarriers can be expected to play a greater role in precision medicine and interdisciplinary applications. These nanocarriers hold the potential to provide safe and efficient novel treatment strategies for complex diseases while promoting cross-border innovation in functional foods and biomedicine, achieving a full-chain breakthrough from basic research to clinical application and industrial translation.

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