Glucan-Based Nanoparticles Empower Precision Cancer Immunotherapy: Design Strategies, Immune Reprogramming Mechanisms, and Clinical Translation Prospects

Introduction

Cancer remains one of the leading causes of mortality worldwide and continues to pose significant challenges in clinical management.¹ Current therapeutic strategies, including conventional chemotherapy, radiotherapy, targeted agents, and endocrine therapies, have somewhat improved patient survival. However, their overall efficacy is limited by several fundamental constraints. These constraints include insufficient tumor specificity,² complex and heterogeneous mechanisms of drug resistance,^1,3–6 the immunosuppressive nature of the tumor microenvironment (TME),⁷ and challenges in managing toxicity during treatment.⁸ Consequently, cancer-associated mortality rates are still unacceptably high. In recent years, cancer immunotherapy has emerged as a transformative therapeutic approach.⁹ Instead of directly targeting tumor cells, immunotherapy engages the host immune system to recognize and destroy malignant cells, thereby facilitating durable tumor control and, in some cases, achieving long-term remission. Unlike traditional cytotoxic methods, immunotherapy aims to disrupt the immunosuppressive networks that tumors establish to evade immune surveillance.¹⁰ Immune checkpoint inhibitors (ICIs), which block inhibitory receptors such as PD-1/PD-L1 and CTLA-4, are pivotal in modern immunotherapy. They reactivate T cell function and foster the development of sustained immunological memory, thus countering tumor immune evasion. Despite these advancements, clinical response rates in most cancer types are modest, generally ranging from 10% to 40%.¹¹ Both primary and acquired resistance are commonly observed,^12,13 the efficacy is limited in immunologically “cold” tumors,¹⁴ and immune-related adverse events raise additional safety concerns.¹⁵ Chimeric antigen receptor T (CAR-T) cell therapy has broadened the scope of immunotherapeutic options by genetically modifying patient-derived T cells to target cancer cells specifically. While CAR-T therapy has shown remarkable success in hematological malignancies, its effectiveness in solid tumors is still limited.¹⁶ Additionally, severe toxicities, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, limit its wider use.¹⁷ These challenges highlight the critical need for precision drug delivery systems that can be controlled spatially and temporally. Such platforms have the potential to increase therapeutic efficacy, reduce systemic toxicity, and address the inherent limitations of current cancer immunotherapies.

Nanoparticles have emerged as sophisticated drug delivery platforms with significant potential to enhance cancer immunotherapy. These platforms operate through diverse and programmable mechanisms that not only enable targeted delivery of immunomodulators but also remodel the TME, augment antigen presentation, and serve as essential components of cancer vaccines.¹⁸ Among the various nanomaterials explored, glucans, naturally derived polysaccharides, have garnered considerable interest due to their outstanding biocompatibility, and inherently low immunogenicity, which establish them as promising immunoregulatory nanocarriers (Figure 1).^19–29 The abundance of hydroxyl groups in glucan structures provides versatile chemical sites for functional modifications,³⁰ facilitating the attachment of various bioactive groups. Dextrans are a class of natural polysaccharides formed by glucose units linked together via various glycosidic bonds. Glucans are broadly classified into two main types based on the stereochemical configuration of their glycosidic linkages. The first type, β-glucans, are primarily derived from fungi (eg, yeast and mushrooms) and cereals.³¹ Their β-1,3-D-glucan backbone forms a distinctive triple-helical structure that is specifically recognized by C-type lectin receptors, such as Dectin-1 and complement receptor 3, which are expressed on innate immune cells.^32–34 Critically, this targeting ability significantly enhances the uptake of nanoparticles by antigen-presenting cells (APCs), including dendritic cells (DCs) and macrophages, thereby facilitating precise delivery of immunomodulatory agents to the TME and promoting effective immune reprogramming. The second type, α-glucans, with dextran being the most notable example, are primarily derived from bacteria and predominantly feature α-1,6 linkages.³⁵ Unlike β-glucans, native dextran is relatively immunologically inert and does not contain Dectin-1 binding motifs, thus providing a “clean” and modular carrier scaffold. Through rational chemical modifications (eg, conjugation of mannose to target CD206⁺ macrophages) or structural changes (eg, incorporation of pH-sensitive acetal linkages), dextran-based nanocarriers can be designed with specific immunological functions, enabling highly customizable and precision-oriented designs.

Figure 1 This timeline provides an overview of research progress on dextran and its derivatives in the fields of drug delivery and tumour immunotherapy from 1861 to 2026, comprehensively illustrating their development from discovery to clinical application.

To date, there have been reviews summarizing advances in dextran biomaterials and various glycan delivery carriers.^19,30 However, most of these focus on material preparation, basic drug delivery, and general applications, with few reviews highlighting the structural and functional differences among various dextran subtypes and their unique roles in immune recognition and the regulation of the tumor microenvironment. Therefore, this paper focuses on the development of glucan nanoparticle systems from the perspective of cancer immunotherapy. It provides a comprehensive discussion and summary covering several key aspects: the rational design and engineering strategies of glucan-based nanoparticles, surface functionalization strategies, immunomodulatory mechanisms, combined immunotherapy strategies, and clinical applications and challenges. By integrating the latest therapeutic approaches and preclinical research, this paper aims to provide new insights for the development of highly effective and safe immunotherapy strategies.

Rational Design and Engineering Strategies of Glucan-Based Nanoparticles

There are two primary methods for obtaining glucans: natural extraction and biosynthesis. β-glucans are typically obtained from fungi, yeast, or grains through hot water extraction, alkali solubilization followed by acid precipitation, or enzyme-assisted extraction,³⁶ α-glucans, on the other hand, are primarily synthesized via microbial fermentation.³⁷ Glucans are predominantly linear polymeric polysaccharides. Stable nanoparticles can only be formed through molecular modification and self-assembly.³⁰

Accumulating evidence demonstrates that glucan-based nanoparticles have transitioned from initial passive delivery vehicles to engineered therapeutic platforms characterized by precise structural tunability and intrinsic immunomodulatory capabilities.^30,38 Through systematic chemical modification, stimuli-responsive structural engineering, and controlled surface functionalization, it is possible to finely tailor their physicochemical properties, in vivo behavior, and immunological outcomes at both molecular and nanoscale levels. This bottom-up rational design paradigm facilitates the programmable integration of structural precision and biological functionality, offering distinct advantages in enhancing targeting specificity, biosafety, and therapeutic efficacy. Collectively, these advances provide a robust engineering foundation for employing glucan-based nanoplatforms in precision cancer immunotherapy.

Chemical Modification Strategies of Glucan-Based Nanoparticles

From a materials engineering perspective, chemical modification is the central strategy for endowing glucans with structural versatility and functional diversity (Table 1). As depicted in Figure 2, oxidation, crosslinking, and grafting are the three most representative and foundational approaches. These methodologies not only expand the structural dimensionality of glucan macromolecules but also establish highly controllable reaction platforms to regulate subsequent self-assembly behavior, stimuli-responsive properties, and biological functionality.

Table 1 Major Chemical Modification Strategies of Dextran-Based Nanoplatforms and Their Applications

Figure 2 Chemical modification strategies of glucan-based nanoparticles. (A) Through three core chemical approaches, oxidation, crosslinking, and grafting, native glucan is endowed with aldehyde-reactive sites, crosslinked network structures, and amphiphilic self-assembly capability. (B) By fine-tuning the degree of oxidation, crosslinking density, and grafting ratio, this platform achieves integration of high drug-loading capacity, structural stability, and immunomodulatory functionality, thereby providing a programmable nanocarrier for precise tumor immunotherapy.

Oxidative Modification: Aldehyde Installation and Structural Programmability

Among various modification strategies, sodium periodate (NaIO₄)-mediated selective oxidation is regarded as one of the most established and frequently utilized methods. This technique selectively oxidizes vicinal diol structures in glucan chains, transforming a portion of hydroxyl groups into highly reactive aldehyde functionalities. Consequently, this introduces programmable chemical sites for subsequent structural construction.⁶⁰ The advantages of this reaction include its compatibility with aqueous environments and mild reaction conditions,⁶¹ which largely preserve the biological activity of the polysaccharide. Oxidized dextran (ODEX) is commonly used as an efficient crosslinking agent. It can react with natural polymers such as chitosan and gelatin to form injectable hydrogels in situ or serve as a shell-forming component in nanocapsule construction.^62,63 Compared to conventional industrial chemical crosslinkers, such as glutaraldehyde,⁶⁴ the in situ oxidation strategy utilizes the native polysaccharide backbone for network formation, significantly reducing potential cytotoxicity risks. As a result, the biocompatibility and safety of the material are substantially enhanced at the design stage.^65–67 Taking the oxidized dextran-doxorubicin/CD147 monoclonal antibody-conjugated oxidized dextran-doxorubicin, (ODEX-DOX/CD147-ODEX-DOX) nanoscale system, blank ODEX at a concentration of 250 mg/L still maintained the survival rate of human umbilical vein endothelial cells and HepG2 cells at over 80%, suggesting that the ODEX carrier itself exhibits low cytotoxicity. Furthermore, after coupling the aldehyde groups with doxorubicin (DOX) and the CD147 antibody, CD147-ODEX-DOX exhibited a tumor DOX enrichment of approximately 20% ID/g in the HepG2 tumor model, which was higher than the approximately 15% ID/g for non-targeted ODEX-DOX and the approximately 7% ID/g for free DOX. Additionally, body weight in the nanoprotec group remained more stable than in the free DOX group, indicating that the oxidation modification not only provides reactive sites for conjugation but also helps improve the therapeutic safety margin through targeted delivery and reduced exposure to off-target tissues.³⁹ However, oxidation with sodium periodate or hydrogen peroxide may disrupt the sugar ring structure of the dextran, leading to a decrease in molecular weight and a reduction in mechanical strength, thereby affecting the material’s stability and processability.^39,40 Notably, the degree of oxidation can be precisely regulated by adjusting reaction conditions, enabling predictable control over the quantity and distribution of aldehyde groups. Related studies have shown that when the ratio of the aldehyde-containing monomer 4-(2-thiiranylmethoxy)benzaldehyde to the copolymer monomer 2-(phenoxymethyl)thiirane was adjusted from 4:6 to 1:9, the final conversion rates of both monomers approached or reached 99%, and the polymer composition was essentially consistent with the initial feed ratio, indicating that the aldehyde content is well-controlled in terms of proportion. At the same time, when the aldehyde content exceeded 40%, the system cured rapidly upon addition of a crosslinking agent and exhibited uneven crosslinking. However, keeping the aldehyde content below 30% resulted in a stably crosslinked polymer. Fourier transform infrared spectroscopy further revealed that the aldehyde C=O peak at 1685.33 cm⁻¹ disappeared after crosslinking, and a C=N peak at 1642.98 cm⁻¹ appeared, suggesting that the aldehyde groups were efficiently converted into imine bonds.⁶⁸ This controllability can lay a stable and reproducible chemical basis for subsequent network construction and the incorporation of functional modules.^61,68

Crosslinking Strategies: Stabilized Network Formation and Functional Integration

The aldehyde groups introduced through oxidation offer highly controllable reactive sites for structural construction and functional modification. Previous studies have shown that these aldehyde functionalities can engage in Schiff base reactions with polyamine-containing molecules to form reversible imine bonds (-C=N-).^69–71 This dynamic covalent interaction facilitates the development of reversible and biocompatible covalent adaptive networks.^63,72,73 Such networks significantly enhance the structural stability of nanostructures during systemic circulation and provide opportunities for integrating multifunctional modules. By harmonizing structural integrity with functional tunability, this crosslinking strategy equips glucan-based nanoparticles with robust stability and a flexible capacity for functional expansion.⁷⁴ Taking the triple-crosslinked dynamic-responsive hydrogel of ODEX-phenylboronic acid grafted polylysine@selenium nanoparticles as an example, the SeNPs had a particle size of 57.44 ± 2.34 nm and a polydispersity index of 0.206 ± 0.051, indicating a relatively uniform nanoparticle distribution. Following the incorporation of SeNPs, the hydrogel pore size decreased from 209.11 ± 14.07 μm to 27.37 ± 3.78 μm, while the tensile strain at break increased from 83.33 ± 3.06% to 142.33 ± 4.51%, indicating that triple cross-linking enhances network density and mechanical stability. Furthermore, after treating various cell types with SeNPs at concentrations ranging from 10 to 1000 μM, cell viability remained above 80% and the hemolysis rate was below 2%, supporting the conclusion that this cross-linking system possesses both structural stability and preliminary biocompatibility.⁷⁵

It is important to note that commonly used crosslinking agents, such as epichlorohydrin and divinylsulfone, have potential cytotoxicity, and their residues may reduce the biocompatibility of the material.^45,46 Furthermore, excessive cross-linking can hinder glucan hydrolysis, prolong the in vivo degradation cycle, and increase the risk of foreign body reactions or chronic inflammation.⁵⁰ Therefore, when designing cross-linking strategies, a balance must be struck between material stability, functional scalability, and biosafety to ensure the controllability and applicability of glucan nanomaterials.

Grafting Approaches: Self-Assembly Induction and Functional Diversification

Hydroxyl-mediated graft modification serves as an efficient strategy for constructing self-assembled nanosystems. Grafting hydrophobic entities, such as cholesterol or polylactic acid, onto the glucan backbone via hydroxyl groups,^76–78 enables the glucan derivatives to spontaneously self-assemble in aqueous environments, forming amphiphilic core-shell nanostructures.^55,79 These structures not only enhance the thermodynamic stability of the system but also significantly improve the loading capacity and in vivo delivery efficiency of hydrophobic drugs. For example, Azadpour et al further demonstrated that ODEX can form covalent bonds with amino sites on the surface of L-arginine-modified magnetic nanoparticles via aldehyde groups. After modification, the material retains its spherical morphology, magnetite crystal phase, and superparamagnetic properties, while simultaneously enhancing its surface functionalization potential and colloidal stability.⁵³ Research by Chung et al also demonstrated that L-arginine-modified dextran nanogels can promote the uptake, storage, and sustained release of antigenic proteins within antigen-presenting cells, as well as enhance cellular and humoral immune responses, suggesting that graft modification can further expand the immunological delivery capabilities of dextran-based nanosystems.⁵⁴ Furthermore, aldehyde groups produced through oxidation can be conjugated with hydrophilic or biomacromolecular components via reductive amination or Schiff base coupling on the particle surface.^39,80 Precise control over oxidation conditions and grafting ratios allows for the simultaneous regulation of particle size, crosslinking density, and surface properties, facilitating the fine-tuned design of the nanosystem’s physicochemical behavior.⁸¹ This tunability is crucial for developing personalized delivery platforms tailored to specific tumor types and therapeutic requirements.

Stimuli-Responsive Engineering of Glucan-Based Nanoparticles

These intelligently engineered stimuli-responsive nanoparticles are designed to maintain structural stability during systemic circulation while generating targeted responses to endogenous or exogenous stimuli. These carriers are capable of undergoing chemical bond cleavage or conformational transitions within specific pathological microenvironments, thereby enabling spatiotemporally controlled drug release. This capability significantly enhances therapeutic precision and safety.^82,83 Based on the unique biochemical characteristics of the TME, pH, reactive oxygen species (ROS), and enzyme-responsive strategies have become the three most mature and widely implemented approaches in designing dextran-based nanoparticles (Figure 3).

Figure 3 Endogenous stimulus-responsive behavior and precise drug release mechanisms of glucan-based nanoparticles. This schematic illustrates that glucan-based nanoparticles remain structurally stable during systemic circulation, while undergoing site-specific degradation within the TME in response to acidic pH (hydrazone bond cleavage), elevated reactive oxygen species (ROS; thioketal bond cleavage), and specific enzymes (peptide bond cleavage). These stimuli-triggered bond cleavages enable controlled degradation of the nanostructure and precise drug release at the tumor site.

pH-Responsive Design: Tumor Microenvironment-Triggered Precision Release

Tumor tissues and intracellular lysosomes typically exhibit mildly to moderately acidic conditions, a consistent physicochemical characteristic that underpins the development of pH-responsive delivery systems.^84–86 This approach usually involves incorporating acid-labile linkages, such as hydrazone and acetal bonds, into the structure of glucan-based carriers. By exploiting the mildly acidic TME (pH 6.5–7.0) and the more pronounced acidity within lysosomes (pH 4.5–5.0), these linkages are cleaved, which triggers the disassembly of the carrier or the release of the drug, thereby facilitating targeted delivery. Previous studies have shown that nanoparticles made from cinnamaldehyde-modified dextran can efficiently release the antibacterial agent glabridin in acidic conditions, achieving precise eradication of intracellular methicillin-resistant Staphylococcus aureus.⁸⁷ Furthermore, Sun et al have developed a nanoplatform that integrates pH responsiveness with a reversible shielding feature, which becomes active in the acidic TME, significantly enhancing cellular uptake efficiency.⁸⁸ Additionally, a dextran-based nanocomposite hydrogel designed for in situ injection has been reported, it initiates drug release through the acid-responsive cleavage of crosslinking bonds within the TME for combined tumor therapy.⁸⁹ However, practical applications must carefully address the potential for nonspecific drug release in physiologically acidic environments, such as the stomach, which could compromise selectivity and diminish the therapeutic safety margin.

ROS-Responsive Design: Oxidative Stress-Driven Therapeutic Amplification

ROS-responsive design is aimed specifically at the high levels of oxidative stress often found in tumor cells and inflamed tissues. This strategy incorporates oxidation-sensitive chemical groups into glucan-based carriers to enable stimulus-triggered drug release. Common ROS-responsive linkages include thioketal and disulfide bonds,^90–92 which cleave under elevated ROS conditions, resulting in the disintegration of nanoparticles and the rapid release of encapsulated therapeutics within cells.⁸⁸

Accumulating evidence has consistently demonstrated the therapeutic benefits of ROS-responsive systems across various disease models. For example, a dextran-thioketal conjugate has been developed that reacts to both elevated endogenous ROS levels and exogenous light irradiation, enabling the synergistic co-delivery of the chemotherapeutic agent doxorubicin and a photosensitizer, thus enhancing the efficacy of combination therapy.⁹⁰ Another study reported a dextran-based nano-self-assembly system that incorporates diallyl disulfide, which enhances the outcomes of photodynamic therapy (PDT) by depleting intracellular glutathione and inducing in situ ROS generation, thereby strengthening antitumor effects.⁹¹ Moreover, nanoparticles made from ODEX and selenocystamine show dual responsiveness to ROS and GSH, enabling precise release of vancomycin at sites of bacterial infection and demonstrating favorable lesion-specific targeting capabilities.⁹² Therefore, ROS-responsive glucan-based nanoparticles are particularly advantageous for tumor or inflammatory microenvironments characterized by pronounced oxidative stress,^83,90 significantly improving therapeutic selectivity and local drug concentration. However, during clinical translation, it is crucial to systematically assess the risk of nonspecific drug release triggered by basal ROS levels in normal tissues, in order to minimize off-target effects and enhance overall safety.

Enzyme-Responsive Design: Lesion-Specific Catalytic Release Mechanisms

Enzyme-responsive design exploits the aberrant overexpression of specific proteases or glycosidases during tumor initiation, invasion, and metastasis. This approach facilitates precise drug release through biomolecule-specific recognition and catalytic reactions. The fundamental principle of this strategy involves incorporating substrate motifs into glucan-based nanoparticle systems. These motifs are designed to be selectively recognized and cleaved by target enzymes, thereby providing high responsiveness and selectivity to the pathological microenvironment. For example, Dosta et al developed a dual-sensitive nanoparticle system by integrating matrix metalloproteinase-cleavable peptide substrate sequences (eg, GPLGVRG) into dextran-based nanoparticles.⁹³ When exposed to tumor-associated proteases, these peptide linkers are specifically cleaved, which triggers structural disassembly and subsequent drug release, significantly enhancing the spatial precision of delivery. Additionally, Meng et al successfully engineered a glycosidase-responsive β-glucan self-assembled nanotube carrier for doxorubicin delivery. In colorectal cancer models, this system demonstrated reduced systemic toxicity and increased antitumor efficacy, while also modulating the gut microbiota, indicating promising potential for integrated therapeutic applications.⁹⁴

Overall, enzyme-responsive glucan-based nanoparticles facilitate targeted drug release through highly specific biocatalytic mechanisms and offer significant advantages in enhancing therapeutic selectivity. However, their efficacy may be limited by variability in the expression levels of target enzymes across different tumor types and among individual patients. Such biological heterogeneity must be carefully considered during system design and clinical translation.

Recent studies suggest that glucan-based stimuli-responsive nanoparticles are evolving from single-trigger systems to multi-stimuli synergistic responsiveness and multifunctional integration.^54,90–92 This trend not only enhances the spatiotemporal precision of drug release but also introduces a novel design paradigm for achieving more effective therapeutic interventions within the complex TME. However, despite these advances, most current preparation methods remain limited to small-scale laboratory production, and it is difficult to maintain batch-to-batch consistency during large-scale manufacturing.^95,96 Furthermore, single-stimulus-responsive designs may result in nonspecific release in healthy tissue, leading to potential off-target effects and compromising treatment safety.^83,93 Meanwhile, multi-stimulus systems are still in their early stages, and little is known about their synergistic or antagonistic effects. Future investigations should systematically evaluate the synergistic and potentially antagonistic interactions among different responsive mechanisms. While improving responsiveness and sensitivity, maintaining structural stability during systemic circulation and ensuring overall biosafety are equally critical. Such efforts will facilitate the advancement of stimuli-responsive glucan-based nanoparticles towards more controllable and clinically translatable therapeutic platforms.

Surface Functionalization Strategies for Cancer Immunotherapy

Surface functionalization represents a critical engineering strategy for modulating the in vivo behavior and immunological effects of nanoparticles. Through precise chemical modification of the particle surface, it is possible to optimize both biodistribution and pharmacokinetic profiles, as well as to confer active targeting capabilities and immunomodulatory functions. These enhancements collectively improve the efficacy and safety of antitumor immunotherapy. Current approaches to nanoparticle surface functionalization fall into three major categories: grafting of targeting ligands, covalent conjugation of immunoadjuvants, and stealth modifications designed to evade immune clearance.

Engineering of Active Targeting Ligands

In tumor immunotherapy, actively targeted delivery is a critical prerequisite for enhancing therapeutic precision. Grafting specific targeting ligands onto the surface of nanocarriers facilitates selective recognition and internalization by tumor cells or lesion-associated cells. This strategy significantly increases localized drug accumulation at the target site while minimizing nonspecific toxicity to normal tissues. Extensive studies have demonstrated that the folate receptor (FR) is overexpressed on the surface of various tumor cells, whereas its expression remains relatively low in most normal tissues.⁹⁷ Leveraging this differential expression profile, folic acid-modified nanocarriers have demonstrated promising targeting capabilities and therapeutic advantages in FR-positive tumor models, including ovarian, breast, lung, and colorectal cancers.⁹⁸ Additionally, the RGD (arginine-glycine-aspartic acid) peptide sequence specifically recognizes αvβ3 integrin, which is highly expressed on tumor vascular endothelial cells and on multiple cancer cell types.⁹⁹ As a result, RGD has been widely employed in nanocarrier surface modification to enable dual targeting of both tumor cells and tumor-associated vasculature, thereby enhancing delivery efficiency and therapeutic efficacy.¹⁰⁰ Beyond these classical ligands, immunoregulatory targeting strategies have also garnered increasing attention. CD47, which is overexpressed on the surface of various tumor cells,¹⁰¹ interacts with signal regulatory protein α (SIRPα) on macrophages. This interaction transmits a “don’t eat me” inhibitory signal to the immune system, thereby suppressing phagocytosis. The conjugation of anti-CD47 antibodies onto the surface of nanocarriers can effectively block the CD47-SIRPα signaling axis, thus restoring macrophage-mediated phagocytic activity against tumor cells and enhancing the innate immune-driven antitumor responses.¹⁰² Within glucan-based systems, the engineering of active targeting has also been extensively explored,¹⁰³ including surface modifications with ligands such as RGD peptides,¹⁰⁴ folic acid,¹⁰⁵ and mannose,²⁴ among others.

Overall, the engineered incorporation of targeting ligands is critical in enhancing the specificity of interactions between nanoparticles and target cells. By promoting selective binding and internalization, this strategy substantially improves the tumor accumulation and delivery efficiency of therapeutic agents. Thus, ligand-mediated surface functionalization can lay a critical engineering foundation for the development of precise tumor immunotherapy.

Covalent Conjugation of Immunoadjuvants for Signal Amplification

Covalent conjugation of immunoadjuvants to the surface of nanocarriers has been extensively explored as a strategy in the realm of nano-immunotherapy in recent years. This method not only improves the in vivo stability of immunostimulatory molecules but also facilitates their targeted accumulation at tumor sites or within APCs. Consequently, this enhances and prolongs the activation of immune signals.

The most commonly used immunoadjuvants for covalent conjugation are agonists of various pattern recognition receptors. Among these, the Toll-like receptor 9 (TLR9) agonist, CpG oligodeoxynucleotide, is particularly effective. It activates plasmacytoid DCs and B cells, triggers the secretion of multiple pro-inflammatory cytokines, and promotes DC maturation and enhanced antigen presentation capacity.¹⁰⁶ Similarly, the TLR3 agonist, polyinosinic-polycytidylic acid [poly(I:C)], mimics viral double-stranded RNA structures and activates both innate and adaptive immune responses, leading to the production of interferons and related cytokines.¹⁰⁷ Additionally, agonists of the stimulator of interferon genes (STING) pathway, when specifically delivered to tumor-associated immune cells, activate the STING signaling pathway and induce type I interferon (IFN-1) responses, offering considerable promise in antitumor immunotherapy.¹⁰⁸

In summary, the covalent conjugation of immunoadjuvants significantly enhances antitumor immunity. It activates APCs, amplifies pro-inflammatory signaling, and reshapes the tumor immune microenvironment. Through these mechanisms, it robustly enhances antigen-specific T cell-mediated antitumor immune responses. This strategy provides a precise and controllable engineering framework for the development of nanovaccines and combined immunotherapy platforms.

Stealth Surface Modification of Nanocarriers and in vivo Behavior Modulation

Under systemic administration, nanoparticles often face rapid clearance by the mononuclear phagocyte system, which compromises their therapeutic efficacy. To extend circulation time and minimize the risk of nonspecific elimination, modifying the surface physicochemical properties of nanoparticles has become crucial.¹⁰⁹ This “stealth” modification is primarily achieved through polyethylene glycol (PEG) coating, which is among the most prevalent techniques. The PEG coating forms a hydrophilic polymeric barrier on the nanoparticle surface, reducing opsonin adsorption through steric hindrance and thus diminishing nonspecific immune recognition and phagocytic uptake.^109,110 However, excessive PEG modification can extend circulation time at the expense of the binding efficiency of targeting ligands and weaken the biological activity of conjugated immunoadjuvants, adversely affecting the therapeutic performance.¹¹¹ Consequently, maintaining a dynamic balance between in vivo stability and functional molecule activity is a significant challenge in designing nano-immunotherapeutic systems.

In summary, the surface functionalization of nanocarriers offers multi-level engineering strategies to enhance tumor immunotherapy. Modifications that target specific ligands improve the spatial precision of delivery, while the covalent conjugation of immunoadjuvants amplifies immune activation signals. Furthermore, stealth modification is crucial for optimizing in vivo behavior. Nevertheless, integrating multiple functional modules often increases structural complexity and may lead to potential functional interference.¹¹² In glucan-based systems, active targeting strategies have become relatively advanced, yet the covalent surface immobilization of immunoadjuvants remains underdeveloped and largely relies on physical encapsulation. Although stealth modification can accommodate targeting modules, overall progress is fragmented and lacks the systematic development seen in mainstream platforms such as poly(lactic acid-co-glycolic acid) or liposomal systems. This gap highlights both the distinctive adaptability of glucan-based materials and the critical challenges that must be addressed. Achieving precise synergy among immune activation potency, spatial targeting accuracy, and prolonged circulation stability is essential for transitioning these nanoplatforms from laboratory research to clinical immunotherapy applications.

To further elucidate the relative advantages and limitations of these design strategies, we provide a comparative overview of their applicability across major cancer types and physiological environments (Table 2).

Table 2 Applicability of Different Design Approaches in Various Cancers or Physiological Conditions

As summarized in Table 1, enzyme-responsive and immunostimulatory designs demonstrate the broadest applicability across different cancer types, while pH- and ROS-responsive systems show strong performance in specific tumor microenvironments but face notable challenges in oral delivery scenarios. This comparison underscores the importance of tailoring design strategies to the intended biological setting.

Immunomodulatory Mechanisms Mediated by Glucan-Based Nanoparticles

The success of tumor immunotherapy is heavily reliant on the effective activation and sustained maintenance of antitumor immune responses, particularly those involving antigen-specific adaptive immunity. However, the immunosuppressive mechanisms prevalent within TME often hinder the full activation of immune effector functions. To address this challenge, recent studies have increasingly combined nanotechnology with immunotherapy, employing glucan-based nanoparticles to modulate the immune microenvironment. These nanoparticles selectively regulate APC functions, reprogram myeloid cell phenotypes, activate innate immune signaling pathways, and target immunosuppressive cell populations. Consequently, dextran-based nanoparticles have emerged as versatile tools for remodeling the tumor immune microenvironment and enhancing the therapeutic efficacy of immunotherapy.

Precision Targeting and Functional Activation of Antigen-Presenting Cells

APCs, especially DCs, are pivotal in initiating adaptive anti-tumor immune responses. The effective targeting and functional activation of these cells are considered critical to the success of tumor immunotherapy.¹¹⁸ In this regard, glucan-based nanoparticles, recognized for their favorable biocompatibility and innate immune recognition capabilities, have shown significant advantages in targeting APCs and co-delivering tumor antigens along with immunoadjuvants (Figure 4).

Figure 4 DC priming and antitumor T-cell immune responses mediated by glucan-based nanoparticles. (A) As a pattern recognition receptor ligand, β-glucan specifically binds to the Dectin-1 receptor on the surface of dendritic cells (DCs), initiating intracellular signaling pathways, inducing DC polarization toward a pro-inflammatory/antigen-presenting phenotype, and participating in the training effect of the innate immune system. Concurrently, β-glucan-based nanoparticles, acting as highly efficient delivery carriers, can encapsulate tumor antigens and immunostimulants, enter DCs via endocytosis, and facilitate the intracellular co-delivery of antigens and immunostimulants. (B) Tumor antigens entering DCs undergo cross-presentation via the MHC class I pathway, forming antigen-peptide–MHC class I complexes that are expressed on the DC surface. This complex binds to the TCR on CD8+ T cells, while co-stimulatory molecules on the DC surface (such as CD80/CD86) bind to the CD28 receptor on the surface of CD8+ T cells, providing critical co-stimulatory signals that synergistically activate CD8+ T cells. The activated CD8+ T cells proliferate and differentiate into cytotoxic T lymphocytes (CTLs), which release effector molecules such as perforin and granzyme to specifically recognize and kill tumor cells expressing the corresponding tumor antigens, effectively inhibiting tumor growth and metastasis.

Natural Receptor Targeting by β-Glucan: Dectin-1-Mediated Trained Immunity

A substantial body of evidence demonstrates that β-glucan can rapidly activate the Dectin-1/Syk/CARD9/NF-κB signaling pathway by binding to the Dectin-1 receptor on macrophages and DCs. This interaction promotes the secretion of pro-inflammatory cytokines.^119–122 Remarkably, it also induces epigenetic reprogramming in monocytes and their differentiated macrophage progeny.¹²³ Mechanistically, the engagement of β-glucan with receptors such as Dectin-1 enhances the expression of long noncoding RNAs, for example, UMLILO,¹²⁴ which then recruits the WDR5-MLL1 complex to the promoter regions of crucial immune-related genes, thereby augmenting H3K4me3 histone modification.¹²⁵ This chromatin-level reprogramming endows innate immune cells with a memory-like functional state known as “trained immunity.” During this process, the chromatin topology of immune-associated genes, including chemokines such as CXCL9 and CXCL10, undergoes remodeling,¹¹³ and the expression of pro-inflammatory cytokines, such as IL-1β, displays enhanced and prolonged kinetics.¹²⁶ These alterations significantly increase nonspecific host responsiveness to tumor antigens and bolster antitumor immune surveillance.^127–130 However, it is important to note that studies have shown that the ability of dextran particles of different sizes to activate Dectin-1 varies. Dextran microparticles (approximately 3 μm in size) and dextran nanoparticles measuring 355 nm can interact significantly with Dectin-1 on the surface of monocytes, whereas 130-nm dextran nanoparticles have a weaker activating effect on this receptor.¹³¹

Engineered Targeting of Dextran: Receptor-Mediated Selective Delivery

Unlike the intrinsic bioactivity of β-glucan, native dextran does not bind to the Dectin-1 receptor and is predominantly internalized by APCs through macropinocytosis. However, this relatively inert characteristic provides a high degree of structural plasticity, facilitating a shift from passive uptake to active targeting through thoughtful chemical modification. One of the most notable strategies is the covalent attachment of mannose moieties to the dextran backbone, resulting in mannosylated dextran. This modified construct demonstrates high-affinity binding to the CD206 (mannose receptor) on M2-type DC subsets, thus enabling precise delivery of antigens or adjuvants.^132,133 An example of a clinically validated application of this targeting mechanism is the FDA-approved lymphatic tracer, Tc-99m Tilmanocept.¹³⁴

Co-Delivery Strategies to Enhance Cross-Presentation and CD8⁺ T Cell Activation

Building upon their targeting capabilities, glucan-based nanodelivery systems have been demonstrated to serve as efficient co-delivery platforms,^54,135,136 enabling the simultaneous intracellular delivery of tumor antigens and immunoadjuvants to APCs.^137–140 This co-delivery strategy facilitates the spatiotemporal coordination of antigen and adjuvant signals, thereby promoting the cross-presentation of antigens via the major histocompatibility complex class I pathway and effectively activating CD8⁺ T cells.¹⁴¹ Previous studies have employed dextran-based constructs to develop artificial antigen-presenting systems capable of inducing the activation and expansion of antigen-specific cytotoxic T lymphocytes (CTLs), resulting in significantly enhanced antitumor immune responses.¹⁴²

Furthermore, co-delivered immunoadjuvants activate key signaling pathways, such as TLRs and STING, leading to the upregulation of costimulatory molecules and pro-inflammatory cytokines on APCs. This process establishes a supportive immunological microenvironment necessary for the complete activation of T cells. For instance, co-delivery systems incorporating STING agonists have effectively enhanced innate immune activation and amplified antitumor efficacy.^143,144

Overall, glucan-based nanoparticles simultaneously enhance efficient tumor antigen presentation and adjuvant-mediated signal amplification, thereby providing both the “first signal” (antigen-specific recognition) and the “second signal” (costimulatory and inflammatory cues) required for complete CD8⁺ T cell activation. This dual-signal synergistic mechanism contributes to overcoming immune tolerance within the TME and induces potent and durable antigen-specific CTL responses.

Remodeling the Tumor Immune Microenvironment: Tumor-Associated Macrophages Reprogramming and Treg Suppression

The immunosuppressive state within the TME constitutes a significant obstacle to effective antitumor immune responses. Specifically, the immunosuppressive network centered on M2-polarized TAMs and regulatory T cells (Tregs) plays a crucial role in facilitating tumor immune evasion.^145,146 Consequently, strategies that involve reprogramming TAM phenotypes and suppressing Treg functions are widely acknowledged as essential for enhancing the efficacy of tumor immunotherapy.

The repolarization of TAMs from an immunosuppressive M2 phenotype to a pro-inflammatory M1 phenotype is a critical step in altering the immunological landscape of the TME. M1 macrophages secrete pro-inflammatory cytokines, such as IL-12 and TNF-α, which promote the activation of effector T cells and strengthen antitumor immune responses.¹⁴⁷ Simultaneously, phenotypic reprogramming of TAMs indirectly suppresses the recruitment and functional maintenance of Tregs. M2-polarized TAMs have been shown to recruit Tregs through the secretion of chemokines such as CCL22 and to sustain their immunosuppressive phenotype through cytokines including IL-10 and TGF-β.¹⁴⁵ Upon repolarization to the M1 phenotype, these immunosuppressive signals are significantly reduced, while the resulting pro-inflammatory environment becomes unfavorable for Treg survival and functional persistence. This alteration effectively disrupts the positive feedback loop of immune suppression mediated by the TAM-Treg interaction within the TME.

At the mechanistic level, various molecular targeting strategies have been deployed to induce TAM reprogramming. For instance, the delivery of small interfering RNA (siRNA) targeting the signal transducer and activator of transcription 6 can inhibit IL-4/IL-13-mediated M2 polarization signaling pathways.^146,148 Furthermore, small-molecule inhibitors such as BLZ-945 can disrupt colony-stimulating factor 1 receptor signaling, thus impeding survival signals essential for M2-type TAMs and diminishing their immunosuppressive functions.¹⁴⁹ Additionally, nanoregulatory strategies that modulate local tumor conditions such as pH, hypoxia, or ROS levels present novel approaches for TAM phenotypic reprogramming.^150–152

In this context, glucan-based nanoparticles, due to their inherent immune recognition properties and multifunctional delivery capabilities, demonstrate significant advantages in modulating the TME. Emerging evidence suggests that these systems can modulate TAM function through multiple mechanisms. These strategies include exploiting surface charge differences to facilitate selective uptake, inhibiting immunosuppressive signaling pathways mediated by macrophage scavenger receptor A (SR-A/CD204), and delivering cytokines (eg, IL-15) or immunostimulatory agents (eg, R848). Consequently, these approaches effectively drive the phenotypic transition of TAMs from an immunosuppressive M2 state to a pro-inflammatory M1 phenotype.^153–155 Specifically, positively charged dextran nanogels have shown superior TAM-targeting efficiency compared to their negatively charged counterparts in breast cancer models, indicating that charge modulation is a critical engineering parameter for optimizing myeloid cell targeting.¹⁵⁶ Sulfated dextran-coated iron oxide nanoparticles selectively target scavenger SR-A/CD204 on macrophages, enabling precise labeling of M2-polarized macrophages and serving as probes for in vivo magnetic resonance imaging (MRI).¹⁵⁷ Moreover, low-molecular-weight dextran derivatives, such as those used in D-TAC technology, specifically target CD206-expressing M2 macrophages and activate their antitumor functions through the delivery of the TLR7 agonist DSP-0509.¹⁵⁸ Similarly, yeast-derived β-glucan particles activate the Syk-Card9-Erk signaling pathway through Dectin-1 engagement, directly inducing the repolarization of M2-type TAMs toward the M1 phenotype.¹⁵⁹

Overall, current research on the regulation of the tumor immune microenvironment by glucan-based systems has largely focused on the phenotypic reprogramming of TAMs. The suppression of Treg function primarily relies on indirect effects resulting from this reprogramming. In contrast, there has been limited research on direct intervention strategies that specifically target Tregs to inhibit their immunosuppressive functions.

Activation and Amplification of Innate Immune Signaling Pathways

Activation of innate immune signaling pathways serves as a crucial bridge connecting innate and adaptive immune responses, playing both initiating and amplifying roles in antitumor immunity. As illustrated in Figure 5, nanodelivery systems enable the precise delivery of immunostimulatory agents to immune cells or within the TME, thereby achieving spatially and temporally controlled activation of innate immune pathways. This targeted modulation provides essential support for the induction of robust and effective antitumor immune responses.

Figure 5 Multidimensional signaling cascade activation in APCs mediated by β-glucan-based nanoparticles. (A) Multireceptor Recognition and NF-κB Pathway Activation: β-Glucan nanoparticles serve as multivalent ligands that simultaneously engage the C-type lectin receptor Dectin-1 and Toll-like receptors TLR2 and TLR4 on the APC membrane. This dual engagement initiates the recruitment and activation of the Syk-CARD9 and MyD88-IRAK signaling axes, respectively. The convergence of these pathways robustly activates the transcription factor NF-κB, initiating the transcription of pro-inflammatory genes. (B) Cytosolic Nucleic Acid Sensing and Amplification of Signaling Cascades: Internalized dsRNA or cytosolic DNA induced by nanoparticles further stimulates the cGAS-STING pathway. Activation of STING promotes TBK1-mediated phosphorylation of IRF3, leading to the production of type I interferons (IFN-I). Secreted IFN-I functions in both autocrine and paracrine fashions through interferon receptors, engaging the JAK-STAT pathway and inducing the expression of interferon-stimulated genes. This pathway synergizes with Toll-like receptor signaling to amplify the signal effectively. (C) APC Maturation and Bridging to Adaptive Immunity: The integrated signaling cascades drive comprehensive APC maturation, characterized by the secretion of pro-inflammatory cytokines (IL-6, IL-12, TNF-α) and the upregulation of co-stimulatory molecules (CD80/CD86). Mature APCs further recruit and activate neighboring DCs through IFN-I and associated mediators, promote antigen cross-presentation, and effectively bridge innate and adaptive immunity, resulting in robust CD4+ and CD8+ T-cell responses.

Nanoregulation of the cGAS-STING Pathway

Within the myriad pathways of the innate immune system, the cGAS-STING axis is pivotal for the detection of cytosolic DNA and the subsequent production of IFN-1.¹⁶⁰ There is a growing body of evidence suggesting that nanodelivery systems can potentiate STING signaling through various mechanisms. These include epigenetic reprogramming strategies, such as the co-delivery of demethylating agents to restore the functionality of the STING pathway.¹⁶¹ Additionally, nanoparticles may either induce DNA damage or promote the generation of immunogenic damage-associated molecular patterns (DAMPs), which facilitate DC cross-presentation and amplify STING-mediated immune responses.¹⁶² These strategies significantly enhance IFN-1 production and have demonstrated efficacy in inhibiting tumor growth and improving survival in multiple tumor models.^162,163 Moreover, nanovaccine systems that combine targeted delivery with microenvironment-responsive properties further improve antigen uptake, lysosomal escape, and cross-presentation by optimizing particle morphology and stimulus-responsive release behaviors, thus counteracting the immunosuppressive TME.^164–166 Although small-molecule cGAS-STING agonists have progressed to clinical trials, the direct activation of this pathway by natural polysaccharides is still uncommon. Notably, Xu et al observed that low-molecular-weight β-glucan derived from brown algae directly enhances cGAS-STING signaling and promotes IFN-1 production.¹⁶⁷ This discovery not only underscores the role of glucans as delivery vehicles but also their intrinsic immunostimulatory capabilities. Such dual functionality underscores their potential in the development of innovative nano-immunomodulators that combine carrier and agonistic properties.

Synergistic Activation of Toll-Like Receptor Signaling

Beyond the STING pathway, TLR signaling is crucial for immune recognition and the initiation of inflammatory responses. Nanoparticle-mediated delivery of TLR7/8 agonists has proven effective in activating the MyD88-dependent signaling cascade, which in turn promotes DC maturation and enhances antitumor immune responses.^168,169

Although the direct use of glucan-based nanoparticles for delivering TLR agonists is still relatively limited, emerging evidence points to their potential advantages in modulating innate immunity. Certain β-glucans can activate the MyD88-dependent NF-κB pathway through TLR2/4 engagement, acting synergistically with Dectin-1 to amplify inflammatory responses.^128,170 Furthermore, interactions between the STING and TLR pathways have been identified, where STING-induced IFN-1 production further enhances TLR-mediated immune signaling.¹⁷¹ Additionally, aminated dextran-coated iron oxide nanoparticles have demonstrated the ability to directly adsorb the complement component C3b, thereby activating the lectin pathway of the complement system.¹⁷²

These findings collectively indicate that the co-delivery of multiple innate immune agonists through glucan-based nanoparticles is a promising strategy for amplifying immune activation signals at various regulatory levels. This approach holds potential for overcoming immune tolerance within the TME and establishing more potent and long-lasting antitumor immune responses.^173–175

Targeted Intervention of Immunosuppressive Cell Populations

The abnormal accumulation of immunosuppressive cells within the TME constitutes a significant obstacle to effective antitumor immunity and plays a critical role in facilitating immune evasion. Among these cells, Tregs and myeloid-derived suppressor cells (MDSCs) are pivotal in the immunosuppressive network. These cell populations employ multiple coordinated mechanisms to suppress the activation of effector T cells and diminish their functional activity, thereby aiding tumor immune escape. Recently, glucan-based nanodelivery systems have shown considerable promise in precisely modulating these immunosuppressive cell subsets,¹⁷⁶ providing innovative approaches to counteract the immunosuppressive TME and reinstate effective antitumor immune responses.

Targeted Modulation of Regulatory T Cells

Aberrant infiltration and sustained accumulation of Tregs within tumor tissues are major contributors to immune tolerance and resistance to immunotherapy.¹⁷⁷ Current research on glucan-based nanoparticles in Treg modulation predominately focuses on the delivery of siRNA targeting immune checkpoint molecules, such as PD-1/PD-L1 and LAG3,^178,179 and on combination strategies that incorporate small-molecule agents like BLZ-945.^88,180 These approaches aim to attenuate Treg-mediated immunosuppression. Beyond checkpoint modulation, a wealth of evidence supports the central role of the transforming growth factor-β (TGF-β) signaling pathway in the differentiation, recruitment, and maintenance of the immunosuppressive function of Tregs.¹⁸¹ As such, targeting the TGF-β signaling pathway is considered an effective strategy to alleviate tumor-induced immune suppression and enhance effector T cell activity. However, the systemic administration of TGF-β inhibitors frequently results in significant off-target effects and systemic toxicity, which limit their clinical applicability.¹⁸² In this context, nanodelivery systems present a viable approach for localized intervention in the TGF-β pathway. For instance, amphiphilic hydroxyethyl starch-polycaprolactone nanoparticles have been used to deliver the TGF-β inhibitor LY2157299 directly to lymphoma lesions, thereby enhancing CAR-T cell functionality.¹⁸³ Similarly, nanoparticles modified with the coagulation-targeting peptide A15, which carry TGF-β inhibitors, have shown pronounced tumor-targeting capabilities and antitumor efficacy.¹⁸⁴ Additionally, metal-lipid hybrid nanoparticles have been employed for TGF-β gene editing, reprogramming the TME into an “immune-activated” state and significantly improving the efficacy of subsequent immunotherapies.¹⁸⁵ Given their favorable biocompatibility and intrinsic immune recognition properties, glucan-based nanoparticles are increasingly recognized as ideal delivery platforms for TGF-β pathway inhibitors. These nanoparticles enable precise, tumor-localized interventions that enhance both safety and therapeutic controllability.

Functional Suppression of Myeloid-Derived Suppressor Cells

MDSCs, along with Tregs, constitute critical immunosuppressive populations that play central roles in tumor immune evasion. MDSCs inhibit T cell activation and effector functions through various mechanisms, including the depletion of essential amino acids such as arginine and cysteine, the production of ROS and peroxynitrite, and the secretion of diverse immunosuppressive mediators.¹⁸⁶ Current interventions targeting MDSCs primarily aim to attenuate their immunosuppressive activities or induce their differentiation into mature myeloid cells. For instance, the delivery of curcumin via self-assembled nanofibers or the administration of all-trans retinoic acid using nanocarriers has been demonstrated to promote MDSC reprogramming. These approaches reduce their recruitment and accumulation within the TME, enhance T cell proliferation and activation, and effectively reverse the immunosuppressive milieu.^187,188 Moreover, nanoparticle-mediated targeting of key immunosuppressive enzymes in MDSCs, such as indoleamine 2,3-dioxygenase 1, has significantly potentiated antitumor immune responses.¹⁸⁹ Collectively, nanodelivery-based strategies, including the delivery of differentiation-inducing agents and the inhibition of critical immunosuppressive enzymes, effectively mitigate MDSC-mediated immune suppression. These strategies do so without substantially impairing normal immune cell function, thereby restoring T cell-mediated antitumor activity.^190–192

Overall, precise interventions targeting immunosuppressive cell populations, including Tregs and MDSCs, represent an important strategy for reversing tumor-induced immune suppression. Glucan-based nanoparticles, by enhancing delivery specificity and reducing systemic toxicity, offer distinct advantages in modulating immunosuppressive cell functions. However, their long-term safety, delivery selectivity, and potential synergistic effects with other immunotherapeutic strategies, such as ICIs or adoptive cell therapies, require systematic evaluation in future studies and clinical translation efforts.

Combination Immunotherapeutic Strategies Enabled by Glucan-Based Nanoparticles

Although tumor immunotherapy has yielded breakthrough outcomes in specific patient populations, monotherapy often fails to address tumor heterogeneity, the immunosuppressive TME, and the emergence of therapeutic resistance. These challenges limit the breadth and durability of clinical responses. Consequently, combination strategies that integrate distinct mechanisms of action have increasingly become a promising approach to enhance overall therapeutic efficacy. By coordinating multiple treatment modalities, it is possible not only to amplify antitumor immune responses but also to reduce the required doses of individual agents, thereby minimizing associated toxicities.

In this context, nanodelivery systems, particularly those functionalized with glucan-based platforms, provide an ideal vehicle for the synergistic integration of diverse immunotherapeutic strategies. Owing to their favorable biocompatibility, programmable structural design, and intrinsic immunomodulatory properties, dextran-based nanosystems enable precise delivery of immunoregulatory agents while simultaneously serving as a “synergistic hub” that bridges distinct therapeutic modalities. Such integration facilitates the transformation of localized therapeutic effects into systemic antitumor immune responses. This section will focus on recent advances and the underlying synergistic mechanisms of glucan-based nanoplatforms in combination immunotherapy strategies, including ICI, photothermal or PDT, and CAR-T cell therapy (Figure 6).

Figure 6 Glucan-based nanoparticle platforms as a central hub for multimodal combinational immunotherapy. This schematic illustrates how the platform integrates ICI, physical and cell-based therapies (e.g, PTT/PDT-induced immunogenic cell death [ICD] and CAR-T cell expansion), and key application pathways within a multi-component programmable delivery system. This platform can enhance local tumor immune activation and improve the response to checkpoint blockade therapy by delivering PD-L1 siRNA, immunomodulatory molecules, or ICD inducers. Concurrently, physical therapies such as PTT/PDT can induce immunogenic cell death in tumor cells, promoting the release of tumor antigens and DAMPs, thereby enhancing APC maturation and T-cell activation. Furthermore, dextran- or mannitol-based nanostructures can be used for in vitro expansion of CAR-T cells, co-delivery of antigens and adjuvants, and remodeling of the tumor immune microenvironment. By modulating immunosuppressive states, training immune cells, and activating effector immune cells, they promote the transition from a “cold” to a “hot” tumor-like immune state in certain models.

Synergistic Strategies with Immune Checkpoint Inhibitors

ICIs have significantly improved clinical outcomes across various tumor types. However, their efficacy as monotherapy is often limited by low response rates and the development of resistance. The integration of ICIs with nanodelivery systems or strategies that induce immunogenic cell death (ICD) presents a promising approach to enhance therapeutic efficacy while reducing systemic toxicity.

Firstly, substantial evidence supports the role of β-glucan as a natural inducer of trained immunity, capable of reshaping innate immune memory through epigenetic reprogramming. This reprogramming effectively counteracts the profoundly immunosuppressive TME. For instance, in refractory models such as hepatocellular carcinoma, β-glucan-mediated immune training has significantly improved ICI responsiveness.¹⁹³ This mechanism serves as an intrinsic driving force for transforming “cold” tumors into “hot” tumors, thus expanding the therapeutic window for checkpoint blockade.

Secondly, at the level of precision delivery, glucan-based nanoparticles serve as efficient carriers for the targeted delivery of anti-PD-1/PD-L1 antibodies or small-molecule immunomodulators to specific tumor tissues or immune cell populations. This targeted approach minimizes systemic exposure and increases the local effective drug concentration within the tumor immune microenvironment. For example, a representative study demonstrated that amine-containing small molecules were grafted onto a dextran backbone through acetal linkages, co-loaded with PD-L1 siRNA, and integrated with imaging probes to create a degradable theranostic nanoplatform capable of real-time visualization and precise gene silencing.²⁶ Similarly, Yan et al designed pH-sensitive amphiphilic poly(β-amino ester) micelles co-loaded with an MDSC inhibitor and a PD-L1 inhibitor. The outer layer was electrostatically coated with dextran sulfate, resulting in a cascade acid-responsive composite nanoparticle. This system effectively prolonged drug half-life, enhanced deep tumor penetration, and comprehensively activated both innate and adaptive immune axes, ultimately achieving significant tumor growth suppression.¹⁵³ Beyond direct drug delivery, glucan-based nanoplatforms can also indirectly potentiate checkpoint blockade by amplifying ICD effects. ICD induction promotes the synchronized release of DAMPs and tumor neoantigens, thereby initiating a robust antitumor immune cascade. Recently, Deng et al developed a photoresponsive camptothecin-loaded dextran nano-immunomodulator, which significantly enhanced ICD in tumor cells through precise control of drug release kinetics.¹⁹⁴ Notably, the combination of ICD inducers with ICIs has been shown to produce pronounced synergistic antitumor effects,¹⁹⁵ effectively reversing tumor-associated immune suppression while inhibiting metastasis and recurrence.

In summary, glucan-based nanoplatforms offer a versatile strategy to overcome the resistance and toxicity associated with ICI by enabling precise delivery of immunomodulators and intelligently integrating ICD-inducing mechanisms.

Integration with Physical Modalities and Cell-Based Therapies

Glucan-based nanoplatforms exhibit unique advantages in integrating photothermal therapy (PTT), PDT, and cell-based therapies. Their principal strength resides in their capacity to transform localized physical or chemical therapeutic interventions into enhanced systemic antitumor immune responses, thus connecting focal treatment effects with sustained immunological activation.

Immunological Synergy Induced by Photothermal Therapy

PTT employs photothermal conversion materials to generate localized hyperthermia upon exposure to near-infrared irradiation, thereby inducing ICD in tumor cells. This process facilitates the release of tumor-associated antigens (TAAs) and initiates an “in situ vaccination” effect.¹⁹⁶ During ICD, calreticulin relocates to the cell surface, and DAMPs such as ATP and high-mobility group box 1 are liberated. Collectively, these signals enhance DC maturation and antigen presentation, leading to the vigorous activation of antigen-specific CTLs.¹⁹⁷

Thus, apart from its direct tumor-ablative capacity, PTT can amplify tumor immunogenicity and restructure the tumor immune microenvironment to promote systemic antitumor immune responses. Nonetheless, the extent of immune activation is significantly influenced by the photothermal conversion efficiency, biocompatibility, and tumor-targeting capability of the photothermal nanoagents.¹⁹⁸ For instance, Jin et al developed a theranostic nanoplatform that, when combined with an anti-PD-L1 ICI, markedly enhanced T-cell infiltration and inflammatory cytokine secretion at tumor sites, while concurrently suppressing the growth of both primary and distant tumors. These findings provide compelling evidence for surmounting resistance to immunotherapy through synergistic PTT-based strategies.¹⁹⁹

Photodynamic Therapy-Driven Systemic Immune Activation

PDT is a noninvasive local treatment strategy for tumors that utilizes photosensitizers to generate ROS when irradiated with light of a specific wavelength. This process results in membrane damage, mitochondrial dysfunction, and programmed cell apoptosis. However, conventional hydrophobic photosensitizers often exhibit poor in vivo stability and limited tumor accumulation, which hampers their broader application in tumor immunotherapy. The use of functionalized glucan-based nanocarriers has been shown to significantly enhance the loading efficiency of photosensitizers and enable controlled biodistribution, thus addressing these limitations and providing a critical material foundation for improving the efficacy of PDT.^200–202

Expanding upon this foundation, Jin et al developed a nanoplatform coated with dextran sulfate that encapsulated the photosensitizer chlorin e6.²⁰³ This system specifically targeted TAMs and generated substantial ROS upon laser irradiation, not only enhancing PDT-mediated tumor cell destruction but also reshaping the tumor immune microenvironment through TAM modulation. This dual functionality facilitated synergistic local tumor ablation and immune activation. The study confirmed the feasibility of using dextran-coated photosensitizers in PDT and suggested that reprogramming myeloid cells may enhance downstream immune responses. Further research has indicated that combining PDT with immunotherapy provides significant benefits in eliciting systemic antitumor immunity.²⁰⁴ Various nanodelivery platforms that integrate PDT with immunomodulatory agents have been effective in suppressing primary tumor growth and in controlling distant metastatic lesions.^205,206 Importantly, the therapeutic effect of PDT is largely confined to the irradiated area. This spatial restriction, when combined with precise control of light exposure, facilitates efficient and localized treatment while minimizing collateral damage to normal tissues, including non-targeted macrophages. In a related development, Wang et al engineered a dextran-black TiO₂ composite hydrogel that integrates PDT with PTT and sonodynamic therapy, significantly enhancing ROS generation and photothermal conversion efficiency. This multimodal platform represents a synergistic approach to local therapy that is particularly effective for infectious wounds and tumors.²⁰⁷

In conclusion, glucan-based PDT platforms exhibit significant advantages when integrated with immunotherapeutic strategies. The further development of systems that enable co-delivery with ICIs could greatly enhance PDT-induced immune activation, leading to robust and durable systemic antitumor responses and potentially eliciting a pronounced abscopal effect against distant metastatic lesions.

Engineering Synergy with CAR-T Cell Therapy

CAR-T cell therapy has demonstrated significant clinical success in treating hematological malignancies. Nevertheless, the conventional manufacturing of CAR-T cells typically depends on intensive ex vivo stimulation to facilitate rapid T-cell expansion. This method can lead to overactivation and functional exhaustion, which may impair the cells’ persistence and antitumor efficacy in vivo, particularly in solid tumors.

To overcome these challenges, Zheng et al developed a dextran-based nanoscale artificial APC platform that efficiently expands functional T cells.²⁹ This platform replicates the natural antigen presentation process, enabling robust T-cell activation while minimizing the exhaustion caused by overstimulation, thus significantly enhancing the therapeutic potential of CAR-T cells. Remarkably, the dextran-based nano-aAPC system demonstrated excellent biocompatibility, showing no apparent cytotoxicity during coculture with T cells. Its nanoscale size facilitates the efficient removal of nano-aAPCs through simple centrifugation and washing steps after T-cell expansion, obviating the need for additional magnetic bead separation. This simplification of the CAR-T cell manufacturing process could reduce the costs associated with clinical translation. Moreover, carboxymethyl dextran-coated magnetic nanoparticles have been used effectively for CD3⁺ T-cell isolation and, when conjugated with antibodies, allow in vivo tracking via MRI, showcasing their theranostic potential.²⁰⁸ Overall, these studies suggest that glucan-based nanosystems, whether through biomimetic antigen presentation platforms or magnetic separation strategies, provide significant advantages in enhancing CAR-T cell expansion efficiency, preserving cellular functionality, and streamlining production processes. These innovations offer promising avenues for addressing the current limitations in solid tumor immunotherapy.

Multi-Antigen/Multi-Adjuvant Co-Delivery and Temporally Programmable Release

The synergistic delivery of multiple antigens and adjuvants, combined with a design that allows for controlled sequential release, has emerged as a pivotal research area in tumor immunotherapy. The essence of this strategy involves encapsulating or conjugating multiple TAAs and immune adjuvants onto a single delivery platform. By responding intelligently to the TME or intracellular stimuli, this approach achieves synergistic and precise activation of the immune system, thereby amplifying the overall effectiveness of immunotherapy.

Various studies have successfully implemented antigen-adjuvant co-delivery strategies using glucan-based nanodelivery systems. For example, vinyl sulfone-functionalized acetalated dextran (Ac-DEX) microparticles have been meticulously engineered to create a broad-spectrum subunit influenza vaccine platform.²⁰⁹ This system employs a “dual-particle” synergistic delivery strategy: the COBRA hemagglutinin antigen is covalently attached to the surface of microparticles to improve antigen presentation efficiency, while the immunoadjuvant cyclic GMP-AMP (cGAMP) is encapsulated within separate Ac-DEX microparticles. Such compartmentalization protects cGAMP from premature degradation in vivo and facilitates its targeted release within the acidic intracellular environment of APCs. Consequently, STING signaling is effectively activated, resulting in a significantly enhanced antigen-specific immune response.

Moreover, integrating glucan-based co-delivery systems with localized delivery modalities, such as microneedles, facilitates site-specific drug release, while minimizing systemic toxicity. Chen et al developed a smart, stimulus-responsive platform that incorporates a microneedle-based delivery strategy.²¹⁰ This system employed acetalated dextran to co-load a hydrophobic photosensitizer (ZnPc) and a hydrophilic ICI (anti-CTLA-4 antibody), which were then integrated into a microneedle array for localized co-delivery. The platform exhibited pH-responsive behavior and demonstrated pronounced antitumor efficacy in animal models, significantly reducing systemic toxicity.

Beyond the benefits of multi-component synergistic delivery, glucan-based nanosystems also offer significant advantages in controlled release and temporally programmed therapeutic design. By modulating crosslinking density, pore architecture, and drug loading modalities, or by incorporating stimuli-responsive elements such as pH, ROS, or enzyme-sensitive linkages, these systems can achieve sustained release and localized retention of therapeutic agents. Such capabilities enable the maintenance of stable immune stimulation intensity, which is particularly beneficial for tumor immunotherapy that requires prolonged intervention. Dosta et al described a dual-sensitive nanoparticle system capable of disassembling under TME-specific conditions and subsequently forming nanogels in situ, thereby significantly prolonging local retention and enabling sustained release of therapeutic agents.⁹³ He et al achieved rapid drug release within the acidic lysosomal environment of tumor cells by tuning the chemical structure and crosslinking degree of dextran.²¹¹ Notably, their system was capable of crossing the blood-brain barrier and maintaining sustained drug delivery at tumor sites, offering a promising strategy for the treatment of central nervous system malignancies, such as glioblastoma. Furthermore, Ma et al developed a dextran-aspirin prodrug nanoplatform that exhibited in situ retention for over 12 hours in colorectal cancer models, continuously releasing salicylic acid. This system exerted long-term antitumor effects by modulating the gut microbiota and inflammatory microenvironment.²¹²

In summary, glucan-based multi-antigen/multi-adjuvant co-delivery systems, with their programmable sustained-release capabilities, enable precise modulation of both innate and adaptive immunity through modular loading and intelligent stimulus-responsive release mechanisms. This integrative design strategy provides a robust engineering foundation for the development of efficient, safe, and durable tumor immunotherapy approaches. However, although most combination therapy regimens have demonstrated good efficacy in preclinical models, few studies have compared the synergistic efficacy, safety profiles, and cost-effectiveness of different combination regimens. It remains to be seen whether the results of many studies can be independently replicated, and there is a lack of standardized evaluation systems for determining optimal dose ratios and administration sequences.

Clinical Applications and Translational Challenges of Glucan-Based Nanoparticles

Preclinical Validation of Therapeutic Efficacy and Safety Profiles

Glucan-based nanoparticles, recognized for their multifunctional properties that combine favorable biocompatibility with significant engineering versatility, have shown effective tumor-targeting capabilities, pronounced antitumor activities, and relatively controllable safety profiles in various preclinical animal models. These results provide a crucial experimental basis for their potential advancement toward clinical translation. Table 3 summarizes the advantages and disadvantages of glucan-based nanoparticles compared to other types of nanoparticles in various applications.

Table 3 Advantages and Disadvantages of Glucan-Based Nanoparticles Compared to Other Common Types of Nanoparticles in Various Applications

Overall, glucan-based nanoparticles are characterized by their safety and biocompatibility.^220,221 However, the biological activity of dextran is influenced by its source, purity, molecular weight, branching degree, solubility, conformation, and particle size. Additionally, they still have shortcomings in terms of mechanical properties, stability, and standardization, which must be addressed through precise engineering design. Furthermore, it is worth emphasizing that the unique value of the glucan-based system lies in its material-immune interface: β-glucan can interact with pattern recognition receptors (such as Dectin-1 and complement receptor 3),²²² while α-glucan primarily serves as a relatively inert and chemically modifiable scaffold, suitable for modular engineering and delivery applications.

In terms of efficacy in animal studies, the primary advantage of glucan-based nanoparticles is their tumor-selective accumulation due to their role as delivery carriers, which leads to enhanced therapeutic benefits. For example, the dextran-dihydroartemisinin-docetaxel dual-drug conjugate system can achieve highly effective tumor suppression in nude mouse xenograft models by improving the in vivo distribution of hydrophobic antitumor drugs. In clinically relevant patient-derived xenograft models, EPI-loaded dextran nanoparticles also demonstrated superior antitumor activity compared to the free drug.²²³ Five days after administration, it achieved a 70% inhibition rate of patient-derived ovarian cancer growth in a mouse model, whereas free EPI achieved only a 40% inhibition rate. This finding is particularly significant as it indicates that glucan-based nanodelivery systems can achieve therapeutic advantages, even in highly heterogeneous tumor models. Similarly, albumin-dextran-coated nanoparticles significantly delayed tumor growth in a murine colorectal cancer model,²²⁴ further substantiating the broad applicability of dextran-based platforms across various tumor types.

Concerning safety, Numerous studies have consistently reported that the administration of glucan-based nanoparticles did not result in significant body weight loss or histopathological damage to major organs in experimental animals.^225,226 For instance, dextran-coated iron oxide nanoparticles have been used for ultra-high-resolution imaging of brain tumor vasculature without inducing evident toxicity in animal models.²²⁷ Furthermore, the stimulus-responsive design not only enhances therapeutic precision but also helps to minimize systemic toxici, for example, pH-responsive fluoxetine-dextran nanoparticles demonstrate favorable safety profiles while supporting both antidepressant and antitumor applications.²²³ Despite excellent efficacy data, the study by Kosnik, W. et al was terminated early due to severe adverse effects, indicating that even in preclinical models, the dextran-based nanoparticle formulation failed to completely eliminate the systemic toxicity of epirubicin.²²⁵ Despite excellent efficacy data, the study by Kosnik, W. et al was terminated early due to severe adverse effects, indicating that even in preclinical models, the dextran-based nanoparticle formulation failed to completely eliminate the systemic toxicity of epirubicin.²²⁸ The optimization of pharmacokinetic behavior is also a crucial mechanism for reducing the toxicity of dextran-based nanosystems. Investigations have shown that dextran-based dual-drug delivery systems significantly extend systemic circulation time and decrease nonspecific distribution to normal tissues, thereby effectively mitigating systemic toxicity.^225,229 Despite excellent efficacy data, the study by Kosnik, W. et al was terminated early due to severe adverse effects, indicating that even in preclinical models, the dextran-based nanoparticle formulation failed to completely eliminate the systemic toxicity of epirubicin.²²³ This result serves as a clear illustration that preclinical efficacy advantages do not equate to safe translation. Toxicity optimization of dextran carriers still faces practical challenges, and one cannot draw the optimistic conclusion that “clinical trials can proceed safely” based solely on tumor suppression data from animal models. Despite excellent efficacy data, the study by Kosnik, W. et al was terminated early due to severe adverse effects, indicating that even in preclinical models, the dextran-based nanoparticle formulation failed to completely eliminate the systemic toxicity of epirubicin.²²⁹

Glucan-Based Formulations Advancing Into Clinical Trials for Cancer Therapy

Although preclinical investigations have provided compelling evidence for the therapeutic potential of glucan-based nanoparticles, the biological differences between animal models and human diseases necessitate their rigorous validation through systematic clinical studies. In this regard, several glucan-related formulations have recently entered clinical evaluation, providing direct insights into their efficacy and safety profiles.

Currently, glucan-derived formulations entering clinical phases are predominantly administered as oral β-glucan or its derivatives. These agents are primarily used as immunomodulators, either as monotherapy or in combination with vaccines, cytokines, or monoclonal antibodies, aiming to enhance antitumor or anti-infective immune responses. Clinical evidence to date suggests that applications of β-glucan in oncology focus primarily on two areas. Firstly, as an immunomodulatory adjunct to chemotherapy, β-glucan has been observed to significantly elevate levels of IL-2, IFN-γ, and CD4⁺ T cells. Notably, patients with low baseline serum granzyme A expression have shown better therapeutic responses and prolonged overall survival. It is important to acknowledge that approximately 30% of patients in this study experienced grade ≥3 treatment-related adverse events, with nausea being the most frequently reported symptom (53.3%).²³⁰ Secondly, in the context of nutritional intervention, β-glucan-fortified oral nutritional supplements have significantly increased energy intake (792.55 kcal/day) and protein intake (40.72 g/day) in patients with advanced malignancies. These benefits were particularly pronounced in individuals with head and neck or upper gastrointestinal cancers, in advanced-stage disease, or in those receiving multiple lines of therapy. Nonetheless, improvements in certain surgical outcome parameters remained limited.^231,232

Table 4 summarizes the bioactive β-glucan formulations that have progressed into clinical trials for cancer therapy. Regarding efficacy and safety data, in high-risk neuroblastoma, the combination of β-glucan as an immunostimulant with anti-GD2 therapy, administered orally in conjunction with the 3F8 regimen, demonstrated good overall tolerability with no significant additive toxicity. Preliminary antitumor signals were observed, providing a safety basis for vaccine combination therapy (NCT00492167).²³³ Differences in study designs across various cancer types also reflect the varying clinical roles of β-glucan. Neuroblastoma studies focus on antigen-targeted immune enhancement. Oral squamous cell carcinoma studies center on regulating MDSCs and improving immune suppression as core endpoints (NCT04387682).²³⁴ HPV-related research targets viral clearance and the resolution of precancerous lesions, falling under the category of preventive interventions (NCT06199128). In lung cancer vaccines, β-glucan is used as an adjuvant in the 1650-G vaccine to enhance immune responses (NCT01829373).²³⁵ Additionally, a Phase II study combining the GD2/GD3 vaccine with β-glucan increased anti-GD2 IgG1 titers without increasing toxicity. However, this did not translate into significant progression‑free survival/overall survival benefits, suggesting that immune enhancement requires more precise dosing schedules and identification of the target patient population (NCT00911560).²³⁶ Overall, neuroblastoma exhibits the strongest link between preclinical mechanisms and trial design, yielding the most reliable signals, due to well-defined targets, clear combination logic, and quantifiable immunological endpoints. For other cancer types, research remains primarily focused on mechanism exploration and lacks standardized efficacy endpoints.²³⁷

Table 4 Bioactive β-Glucan Preparations That Have Entered Clinical Trials for Cancer Treatment

In summary, these clinical studies provide preliminary evidence supporting the immunomodulatory potential of glucan-based formulations, their limitations, including small sample sizes, relatively short follow-up periods, and some endpoints failing to reach statistical significance, underscore the necessity for larger-scale, rigorously designed randomized controlled trials to more definitively establish their clinical value.

In addition, dextran, an α-glucan, is extensively utilized in clinical settings, particularly in iron formulations and combination supportive therapeutic systems. Dextran-based formulations and β-glucan immunotherapy trials serve different clinical purposes. β-glucan is typically used to enhance or modulate immune responses, whereas dextran primarily functions as a carrier, chelating matrix, or lymphatic tracing platform in these studies.^238,239 Table 5 presents an overview of dextran (α-glucan)-based formulations that have entered clinical trials for cancer-related applications.

Table 5 Dextran (α-Glucan) Formulations That Have Entered Clinical Trials for Cancer Therapy

As presented in Table 5, the trials included herein focus not on direct antitumor efficacy such as tumor regression, progression-free survival, or overall survival, but on sentinel lymph node identification, diagnostic accuracy, procedural feasibility, and administration safety. Among these, Tc‑99m‑tilmanocept represents a representative dextran‑based agent with relatively mature clinical evidence. It is structured with a dextran backbone conjugated to mannose ligands and DTPA chelating groups, enabling targeting of lymph node macrophages or dendritic cells via mannose-CD206 recognition. Studies in breast cancer, melanoma, and head and neck tumors have mainly evaluated its detection performance and safety in sentinel lymph node localization, demonstrating the clinical value of dextran as a precision tracing platform (NCT00671918; NCT01106040; NCT02287675; NCT04261179).²⁴⁰ Research in colorectal cancer, endometrial cancer, pediatric solid tumors, and Kaposi’s sarcoma has further expanded its applications to lymphoid tissue targeting, PET/CT imaging, special‑population localization, and lymphatic drainage mapping (NCT01902953; NCT05446324; NCT02509598; NCT02201420; NCT03157167). Studies in oral squamous cell carcinoma have also combined sentinel lymph node biopsy with personalized neck radiotherapy strategies, suggesting that such tracers can contribute to the optimization of treatment decisions (NCT07121595).²⁴¹

The reason these trials tend to yield clear clinical signals is primarily the direct correlation between material structure, mechanism of action, and clinical endpoints. Overall, the clinical advantages of dextran lie not in direct immune activation, but in its preclinical properties, such as high modifiability, the ability to conjugate with targeting ligands, and biocompatibility. These features directly support its successful translation into lymphatic tracing and drug delivery systems, with a clear translational pathway and high degree of standardization.

Practical Constraints, Regulatory Challenges, and Manufacturing Bottlenecks

Although glucan-based nanoparticles have demonstrated positive results in most preclinical studies, their further translation into clinical applications faces multiple practical challenges. First, their efficacy is highly system- and model-dependent and is not consistently reliable across all experimental designs.^28,242,243 Differences in dosing regimens and tumor immunogenicity can lead to varying degrees of efficacy. Furthermore, even minor variations in particle size, structure, and preparation methods can significantly affect targeting and immunogenicity, potentially leading to insufficient reproducibility across studies or differing clinical trial outcomes among various cancers. Additionally, current research remains primarily focused on short-term efficacy and acute toxicity assessments. Their long-term safety, chronic immunological effects, and stability under different physiological and pathological conditions still require validation through more systematic and standardized studies. In addition, from a regulatory standpoint, there is currently no universally accepted definition of nanomedicine, nor is there a standardized framework. This misalignment may lead to inconsistent characterization methodologies and consequent delays in the approval processes for clinical trials.^96,244 In terms of large-scale manufacturing, the selection of starting materials, ensuring batch-to-batch consistency, and the standardization of critical quality attributes significantly heighten the complexity of clinical translation and commercial-scale production.²⁴⁵ Furthermore, further research is needed to determine how to effectively integrate dynamic control strategies into the industrial production process of glucan-based nanomedicines.⁹⁵

In summary, most current studies remain at the stage of in vitro cell experiments and animal studies. Although glucan itself has been approved for use in certain anticancer applications, glucan-based nanoparticles as a novel tumor immunomodulatory delivery system still lack essential research data for clinical translation. These data include large-scale preparation processes, in vivo distribution characteristics, and pharmacokinetic profiles. Therefore, there is still a long way to go before they can be used in actual clinical practice.

Conclusions and Future Perspectives

Glucan-based nanoparticles, characterized by their intrinsic immunomodulatory properties and high engineering versatility. Extensive preclinical studies have shown that these nanosystems can remodel the tumor immune microenvironment at multiple levels. They achieve this by targeting immunosuppressive cell populations, enhancing antigen presentation efficiency, amplifying innate immune signaling, and synergistically activating adaptive immune responses.

As a result, they significantly enhance the overall efficacy of immunotherapy. We have innovatively developed a comprehensive review framework for glucan-based nanoparticle tumor immunotherapy that focuses on specific diseases, delves into underlying mechanisms, leads the field, and is translation-oriented, thereby addressing the gaps and shortcomings in existing reviews.

The heterogeneity of the nanotumor microenvironment,²⁴⁶ immune responses, and drug clearance mechanisms vary significantly across different species.²⁴⁷ Consequently, the differences between preclinical models and the human physiological environment are the primary reason for difficulties in translation. Therefore, the pharmacokinetic and pharmacodynamic profiles of glucan-based nanoparticles in mouse or rat models cannot be directly extrapolated to humans. Furthermore, from a materials science perspective, glucan-based nanoparticles still face several structural and chemical limitations. The significant steric differences among dextran hydroxyl groups result in poor grafting controllability and substantial performance variations between batches of reaction products.⁵³ Additionally, the varying reactivity of hydroxyl groups at different positions leads to heterogeneous hydrophilicity and degradation behavior in the nanoparticles, thereby affecting their in vivo pharmacokinetics and functional performance.⁵⁹

Despite these challenges, certain highly engineered dextran-derived systems (such as Ac-DEX micro/nanoparticles) have demonstrated excellent versatility and scalability, providing a solid foundation for clinical translation. Overall, dextran-based nanoparticles offer a multi-level intervention strategy for reversing the tumor immunosuppressive microenvironment, and their application prospects are promising. However, further improvements are needed in terms of standardized preparation, safety assessment, elucidation of mechanisms of action, and translational research.

Against this backdrop, future research should focus on several key areas to further enhance the translational potential of glucan-based nanotherapeutics. First, regarding the targeted intervention of immunosuppressive cell populations, further research should concentrate on improving the selectivity of glucan-based nanosystems for Tregs and MDSCs. The incorporation of response modules that are highly sensitive to specific enzymes, metabolites, or lesion-associated signals could enable precise modulation of the immunosuppressive network. This approach minimizes unintended interactions with normal immune cells and broadens the therapeutic safety margin. It should also be noted that increased target specificity may be accompanied by unintended immune interference or side effects, necessitating the validation of safety thresholds across multiple preclinical models. Second, it remains unclear whether glucan-based nanoparticles exert selective and specific regulatory effects on other tumor-associated immune cell populations, such as DCs and natural killer cells. Advanced methodologies, including single-cell sequencing-based multi-omics approaches, are crucial for delineating these cell-type-specific interactions in forthcoming research. Moreover, the development of multifunctional integrated nanosystems continues to be a vital pathway for enhancing therapeutic efficacy. Future platforms based on dextran should increasingly adopt modular design principles, facilitating the coordinated delivery of multiple immunoadjuvants, immunomodulatory agents, or therapeutic drugs within a single system. Such strategically programmed amplification and integration of immune signals are imperative to effectively address tumor heterogeneity and its dynamic evolution. Importantly, the clinical translation of these technologies will ultimately determine the realization of significant advancements in this field. The complexity of multifunctional systems may also increase production difficulties, quality control challenges, and potential toxicity risks. Comprehensive assessments of in vivo immunogenicity, metabolic fate, and long-term safety of glucan-based nanodelivery systems are essential. Additionally, the establishment of standardized quality control frameworks and optimization of administration routes will significantly impact regulatory approval and clinical applicability. Furthermore, given the rapid advancements in mRNA vaccines, personalized tumor antigen identification, and emerging immunoregulatory technologies, the potential applications of glucan-based nanoplatforms in next-generation cancer vaccines and combination immunotherapy strategies deserve particular attention.

In summary, glucan-based nanoparticles have evolved beyond mere delivery vehicles into sophisticated engineered therapeutic platforms that actively engage in immune modulation. With the ongoing integration of materials science, immunology, and clinical oncology, these systems are set to play a pivotal role in precision tumor immunotherapy. Their development holds substantial promise for fostering efficient, safe, and sustainable cancer immunointervention strategies.