Abstract
The pronounced heterogeneity and immunosuppressive characteristics of the tumor immune microenvironment (TIME) substantially impede the clinical efficacy of immune checkpoint blockade (ICB) therapies. Biomacromolecules-such as antibodies, cytokines, and nucleic acids-have emerged as powerful tools for precisely modulating immune responses within the TIME. However, their clinical translation remains challenging due to inherent limitations, including enzymatic degradation, systemic toxicity, off-target effects, and poor tumor accumulation. Injectable hydrogels represent a promising platform for the spatiotemporal delivery of biomacromolecular therapeutics, enabling localized, controlled, and sustained release. Their structural versatility allows for the co-delivery of multiple bioactive agents and nanoparticle-based drugs, with tunable release kinetics tailored to therapeutic needs. In this review, we propose a three-tiered delivery strategy framework based on injectable hydrogels, reflecting the progressive evolution of delivery functionality. We systematically categorize hydrogel-mediated biomacromolecule delivery into three major types-proteins, nucleic acids, and glycans-highlighting their mechanisms of spatiotemporal release and immunomodulatory functions in the TIME. Additionally, we critically examine existing barriers to clinical translation and discuss how artificial intelligence (AI) can be leveraged to optimize hydrogel formulation and predict synergistic antitumor effects. Finally, we explore the integration of organoid platforms and humanized animal models to establish more physiologically relevant evaluation systems for hydrogel-based delivery platforms. These advances collectively aim to accelerate the clinical translation of hydrogel-mediated biomacromolecule delivery systems and facilitate next-generation precision immunotherapies for cancer.
Graphical abstract
Keywords: Injectable hydrogels, Biomacromolecule delivery, Tumor immune microenvironment, Spatiotemporal release, Artificial intelligence-driven design
Introduction
The advent of ICB therapy has marked a transformative milestone in cancer immunotherapy. However, its efficacy is significantly constrained by TIME, with durable responses observed in fewer than 30% of patients [1]. TIME represents a complex network of cells and molecules within tumor tissues, exhibiting dual immunoregulatory functions. On one hand, antitumor components, such as dendritic cells (DCs), M1 macrophages, and cytotoxic T lymphocytes (CTLs), perform immune surveillance through antigen presentation or direct tumor cell elimination. On the other hand, immunosuppressive elements, including regulatory T cells (Tregs) and M2 macrophages, foster an immunosuppressive milieu by secreting cytokines like IL-10 and TGF-β, which not only promote tumor immune evasion but also directly undermine the efficacy of immunotherapy [2].
While “hot” tumors, characterized by abundant immune-inflammatory cells, respond favourably to immunotherapy, “cold” tumors—marked by absent or exhausted T cells—exhibit treatment resistance due to their immunosuppressive microenvironment [3]. Current research efforts focus on restoring immune balance in TIME through strategies such as targeted Treg depletion, colony stimulating factor 1 receptor (CSF1R) inhibition, or stimulator of interferon genes (STING) pathway activation [4]. Moreover, biomacromolecules, including anti-PD-1 antibodies, IL-15/granulocyte macrophage-colony stimulating factor (GM-CSF), and programmed cell death ligand 1 (PD-L1)-targeting siRNA, hold significant promise for precise TIME modulation [5–7]. However, the effective delivery of these molecules to enhance antitumor immunity faces substantial hurdles. These stem from inherent limitations in biomacromolecule druggability, such as short in vivo circulation half-life, susceptibility to enzymatic degradation, and poor delivery efficiency due to limited tissue permeability [8–13]. Additionally, molecule-specific issues arise: proteins and glycans often induce systemic toxicity and off-target effects upon systemic administration, while nucleic acid/protein-based therapeutics suffer from insufficient tumor accumulation due to nuclease degradation and rapid clearance [14, 15]. Compounding this, the spatiotemporal heterogeneity of TIME renders single-agent delivery strategies prone to inducing therapeutic resistance [16]. These challenges severely impede the clinical translation of biomacromolecule drugs, highlighting the urgent need for precision delivery systems capable of effectively regulating drug release kinetics to balance therapeutic efficacy and safety for targeted TIME modulation.
Injectable hydrogels, which are cross-linked either chemically (e.g., through dynamic covalent bonds) or physically (e.g., via ionic and hydrogen bonds) [17], offer a promising solution. External stimuli, such as temperature, pH, and ion concentration trigger the cross-linking of the precursor solution, enabling in situ sol-gel transformation after injection and thereby enhancing drug loading efficiency [18, 19]. This localized drug release maintains therapeutic concentrations at the target site, enhances efficacy, and minimizes systemic toxicity [20–23]. Their unique three-dimensional porous network structure and controllable biodegradability not only protect diverse therapeutics, including biomacromolecules (antibodies, nucleic acids, cytokines), but also govern their release profiles, making them widely applicable in local tumor drug delivery. Furthermore, their inherent environmentally responsive properties enable the synergistic release of multiple bioactive agents for precise TIME manipulation [24]. For instance, hydrogel networks can be engineered for programmable release kinetics (sustained release over 7–28 days), concurrently inducing immunogenic cell death (ICD) through rapid toll-like receptor (TLR) agonist release to activate DCs, while maintaining drug concentrations to support long-term CD8⁺ T cell expansion. This aligns with the temporal phases of immune response—activation, maintenance, and memory [25, 26]. Their superior multi-drug synergy allows for the co-delivery of agents like the STING pathway activator cGAMP and anti-PD-1 antibodies, activating the STING pathway while simultaneously relieving T cell inhibition, thereby enhancing CD8⁺ T cell infiltration and activation [27]. Additionally, ROS-responsive hydrogels co-delivering nanodrugs and anti-PD-1 antibodies can induce ICD, activate DCs, and further augment CD8⁺ T cell infiltration [28].
The spatiotemporal control offered by injectable hydrogels holds significant promise in advancing tumor immunotherapy towards an “on-demand responsive” precision paradigm, thereby overcoming the clinical translation barriers of biologics. This review innovatively establishes a three-tiered delivery strategy based on injectable hydrogels for biomacromolecule delivery to modulate TIME. It systematically analyses the spatiotemporal control mechanisms and immunoregulatory advantages of these strategies across various classes of biomacromolecules, including proteins, nucleic acids, and glycans. Additionally, we critically examine existing challenges and explore the potential of AI-driven hydrogel design optimization and organoid/humanized model-integrated evaluation systems to enhance therapeutic outcomes. Overall, this review provides a comprehensive insight into how to leverage injectable hydrogels to achieve precise and effective TIME modulation in cancer immunotherapy.
Biomacromolecule modulation of TIME
Biomacromolecules, comprising proteins, nucleic acids, and carbohydrates (such as polysaccharides and glycoproteins), serve as the fundamental structural and functional units of living organisms. They orchestrate the dynamic balance and adaptive evolution of biological systems through mechanisms like catalytic reactions, mechanical support, signal transduction, and immune regulation [29–31]. Within the pathological ecosystem of the TIME, biomacromolecules exhibit functional heterogeneity, playing dual roles in both tumor promotion and suppression. By precisely modulating in the spatiotemporal distribution of these biomacromolecules, it is possible to reshape the immune-suppressive landscape of the TIME, thereby restoring anti-tumor immune responses. This section focuses on key types of bioactive macromolecules and their roles in either promoting or inhibiting tumor development.
Protein-based therapeutics
Among the various classes of biomacromolecules, protein-based therapeutics represent one of the most successful and widely applied strategies in cancer immunotherapy to date. These agents precisely modulate the function of immune cells within the TIME by participating in signal transduction, metabolic regulation, and immune responses. Based on their mechanisms and structures, they can be primarily categorized into therapeutic antibodies, cytokines, and chemokines.
Therapeutic antibodies
Antibody drugs play a key role in cancer immunotherapy by specifically targeting tumor antigens or immune checkpoints, thereby activating the immune system to eliminate tumor cells. This category includes monoclonal antibodies, bispecific antibodies, and antibody-drug conjugates (ADCs) [32].
Monoclonal antibodies, the earliest-developed type of antibodies, comprise murine, chimeric, humanized, and fully human types. They primarily induce cancer cell death through highly specific binding to target antigens, via either direct or indirect mechanisms. For example, Rituximab (anti-CD20) specifically binds to CD20 and triggers various effector pathways to directly eliminate B cells. It was also the first approved monoclonal antibody therapy for B-cell non-Hodgkin lymphoma [33]. Immune checkpoint inhibitors such as Pembrolizumab (anti-PD-1) and Ipilimumab (anti-CTLA-4) act indirectly by activating T cells [34, 35]. These antibodies can specifically block escape pathways, reshape the functional state of T cells within the TIME, and enhance anti-tumor immune responses [32, 36, 37].
Bispecific antibodies (BsAbs) are engineered to bind two different antigens simultaneously. Prominent examples include T cell engagers (e.g., CD3 × tumor antigens) and immune checkpoint combinations (e.g., PD-1 × CTLA-4), which enhance specific immune activation [32, 35]. For example, Cadonilimab is a bispecific antibody that targets PD-1 and CTLA-4 and has shown significant clinical benefits in advanced cervical cancer [38]. Nevertheless, challenges such as its short half-life and toxicities like cytokine release syndrome (CRS) still need urgent attention [39].
ADCs consist of three components: a targeting antibody, a linker, and a cytotoxic payload. They enhance the killing effect by precisely delivering the drug to cancer cells. For example, trastuzumab deruxtecan (T-DXd) uses a cleavable linker and the topoisomerase inhibitor DXd. This ADC can trigger ICD, promote dendritic cell maturation, and activate T cells [40, 41].
Cytokines
Cytokines are small signaling proteins, typically with a molecular weight of 5–25 kDa, produced by various immune cells and non-immune cells. Cytokines play a key role in immune regulation, inflammatory response, and the TIME [42, 43]. They regulate the proliferation, differentiation, and effector functions of immune cells, such as the activation of cytotoxic T cells and NK cells, by activating signaling pathways like JAK/STAT and NF-κB [44–46]. IL-2, the first cytokine approved by the FDA for cancer treatment (for metastatic renal cell carcinoma in 1992 and melanoma in 1998), promotes T-cell differentiation and induces the secretion of IFN-γ and granzyme B via activation of the JAK/STAT pathway (particularly STAT5) [47]. Following the clinical approval of IL-2 and IFN-α [48], subsequent clinical trials have largely focused on IL-2, IL-15, IFN-α, and GM-CSF [49]. Over 60% of these trials target cancer therapy, with IL-2 and GM-CSF frequently explored in combination with chemotherapy or immune checkpoint inhibitors [42].
Cytokine therapy has great potential in overcoming tumor immune suppression and enhancing anti-tumor responses, but it still faces challenges such as toxicity, short half-life, and limited efficacy. Taking IL-2 as an example, it was approved by the FDA for treating renal cell carcinoma as early as 1992. However, its high-dose application often causes severe toxic reactions, such as vascular leakage syndrome [42, 50]. In recent years, research on new cytokines such as IL-15 and IL-12 has frequently employed local delivery strategies to reduce systemic toxicity [42, 51]. In this context, hydrogels have attracted attention as typical carriers for local delivery. For example, the Liang team developed an immunostimulatory thermosensitive hydrogel that reprograms the tumor microenvironment by locally delivering GM-CSF and the nano-platform TCCaN. This approach provides a new strategy for systemic cancer immunotherapy while significantly enhancing the safety and targeting of cytokine therapy [9].
Chemokines
Chemokines are small secretory proteins in the cytokine superfamily that play a key role in cancer immunity by regulating the migration of immune cells and the TIME. They have dual functions: they can either promote tumor development (such as recruiting immunosuppressive cells) or enhance antitumor immunity (such as attracting effector cells) [52]. Anti-tumor chemokines (such as the CCR5-CCL5 and CX3CR1-CX3CL1 axes) can recruit antitumor immune cells such as CD8⁺ T cells, Th1 cells, and NK cells to the tumor microenvironment [52–57]. In contrast, immunosuppressive chemokines (such as the CCL2/CCR2 axis) recruit MDSCs and TAMs to build an immunosuppressive barrier, while the CXCL12/CXCR4 pathway hinders T cell infiltration by recruiting stromal cells [52, 58, 59].
Anti-tumor chemokine therapies are mostly in preclinical or early trial stages. For example, in NSCLC patients, a DC vaccine expressing CCL21 (NCT01574222) used as monotherapy increased CD8+ T cell infiltration and tumor-specific immune responses [60]. As protein-based therapeutics, chemokines exhibit common limitations such as poor stability and significant off-target toxicity, which severely restrict their clinical translation in tumor immunotherapy. To overcome these limitations, current research primarily focuses on strategies like nano-carrier encapsulation and local sustained-release delivery to overcome application bottlenecks [61]. For instance, Guan et al. innovatively constructed an injectable thermoresponsive hydrogel delivery system for the controlled release of CCL25. This system can efficiently recruit CCR9+CD8+ T cells through precise dose- and time-dependent regulation, significantly reshaping the tumor microenvironment of triple-negative breast cancer and thereby synergistically enhancing the antitumor immunotherapy effect of PD-1 inhibitors [62].
In summary, protein-based therapeutics—including antibodies, cytokines, and chemokines—form a cornerstone of modern cancer immunotherapy. While their clinical impact is substantial, challenges such as systemic toxicity, short half-life, and inadequate tumor-specific delivery remain. These limitations highlight the critical need for advanced delivery strategies to fully realize the potential of this powerful class of drugs.
Nucleic acid-based therapeutics
Nucleic acid-based therapeutics have emerged as a versatile and powerful class of agents for cancer immunotherapy. They function through two primary mechanistic dimensions: modulating innate immune responses and directly intervening in gene expression [63]. The main categories include messenger RNA (mRNA), plasmid DNA (pDNA), small interfering RNA (siRNA), microRNA (miRNA), CRISPR-Cas9 systems, and aptamers [10, 64, 65].
A key inherent property of many nucleic acids is their ability to act as potent agonists of pattern recognition receptors (PRRs), thereby stimulating the innate immune system [66, 67]. For instance, tumor-derived DNA can activate the cGAS-STING pathway to bolster anti-tumor immunity [10]. Synergistic combinations, such as TLR agonists (e.g., Poly-I: C, CpG ODN) with cGAS-STING activators, can achieve potent activation of both innate and adaptive immunity [68–71].
The second major function involves the direct regulation of gene expression. This can be achieved either by introducing genetic material that encodes for immunostimulatory proteins (e.g., using pDNA or mRNA) or by silencing specific genes that play roles in immune suppression (e.g., using siRNA or antisense oligonucleotides/ASOs).
mRNA and pDNA platforms enable the in vivo expression of tumor antigens, immune modulators, or therapeutic proteins, forming the basis for cancer vaccines and gene therapies. mRNA vaccines, in particular, have garnered significant attention due to their rapid development and high efficacy in encoding tumor-associated antigens (TAAs) or neoantigens for personalized vaccines [72–74]. For example, the IVAC MUTANOME trial (NCT02035956) used personalized mRNA vaccines to induce neoantigens-specific CD8+ T cell responses in melanoma patients, demonstrating synergy with immune checkpoint inhibitors [75]. Beyond antigens, mRNA can be engineered to encode immune-stimulatory cytokines like IL-12 to enhance local immune activation [76, 77]. Similarly, pDNA can be designed to express tumor-specific antigens, cytokines, or chimeric antigen receptors (CARs) in target cells [78]. One innovative study used nanocomposites to deliver pDNA encoding IFN-γ and an anti-ALK CAR to tumor-associated macrophages, promoting their polarization to the pro-inflammatory M1 phenotype and enhancing phagocytosis of neuroblastoma cells, which suppressed tumor growth and prolonged survival in mouse models [79].
Gene silencing strategies primarily utilize siRNA, miRNA, or ASOs to downregulate the expression of target genes. ASOs are single-stranded oligonucleotides that mediate target mRNA degradation via RNase H recruitment or act through steric hindrance [74, 78]. Similarly, siRNA and miRNA are double-stranded RNAs that silence gene expression via the RNA interference pathway. In cancer immunotherapy, these modalities are commonly deployed to silence immunosuppressive genes—such as PD-1, CTLA-4, PD-L1, or TGF-β—thereby enhancing anti-tumor immunity [80–83]. For instance, Xu et al. knocked down TGF-β expression using siRNA to alleviate immunosuppression and improve the efficacy of melanoma immunotherapy [84].
miRNA therapeutics, including mimics to restore lost tumor-suppressor functions and inhibitors (antagomirs) to block oncogenic miRNAs, also modulate the TIME. A notable example is the miR-34a mimic MRX34, which in preclinical models reduced PD-L1 expression and enhanced CD8+ T cell infiltration [85, 86]. Conversely, the inhibitor MRG-106 targets oncogenic miR-155 to restore T cell activity and has advanced to clinical trials for lymphoma [87].
Gene editing technologies, particularly CRISPR-Cas9, enable permanent gene knockout or correction. In immunotherapy, CRISPR is applied to engineer immune cells (e.g., generating PD-1 knockout T cells with enhanced anti-tumor activity) or to directly target oncogenes within the tumor [88].
Aptamers are single-stranded oligonucleotides that can specifically bind to target proteins and modulate their function through mechanisms such as blocking interactions, promoting degradation, or inhibiting enzymatic activity. In tumor immunotherapy, they can act as antagonists or agonists of immune receptors [78]. Notably, Ren et al. used liposomes to deliver a PD-L1-targeting– aptamer to melanoma cells, effectively remodeling the TIME and enhancing anti-tumor immunity [89].
Despite their immense potential, the clinical translation of nucleic acid therapeutics is hampered by challenges including poor stability, inherent immunogenicity, and inefficient in vivo delivery [90]. Advanced delivery systems, such as hydrogels and nanoparticle-hydrogel composites, are being actively developed to overcome these barriers, enhancing local retention, reducing systemic toxicity, and improving targeting efficiency [10].
Glycan-based therapeutics
Glycan-based therapeutics, such as polysaccharides, glycoproteins, and glycolipids, regulate the immune system in various ways and play a crucial role in cancer treatment by exerting anti-tumor effects [91, 92]. These molecules are widely obtained from sources such as algae, bacteria, fungi, and plants [92, 93]. Their mechanisms include activating immune cells, regulating cytokine secretion, and modulating signaling pathways, which together enhance the body’s anti-tumor immune response [94–96].
Polysaccharides have become a promising research direction for immunomodulatory drugs in recent years, including astragalus polysaccharides and ganoderma polysaccharides. They can enhance the activation, maturation, and functional polarization of macrophages and dendritic cells, thereby improving their antigen presentation ability and local cytokine secretion levels. This process initiates and amplifies the anti-tumor immune response and reverses the immunosuppressive characteristics of the TIME [97–99]. Moreover, it is worth noting that polysaccharides, as natural polymers, have advantages such as good biocompatibility and low toxicity, and are often developed as hydrogel carriers, such as chitosan, to achieve drug delivery functions [100, 101].
In addition to polysaccharides, other glycoconjugates, such as glycosphingolipids and glycoproteins, are also being actively explored for their roles in tumor vaccine development and TIME modulation [102]. Among glycolipids, lipopolysaccharides (LPS) are notable for their ability to activate innate immunity via TLR4 [103], inducing macrophages to secrete tumor necrosis factor (TNF) and directly kill tumor cells [104]. Notably, the inflammatory response triggered by LPS through the TLR4/NF-κB signaling pathway has dual effects: moderate activation may enhance antitumor immunity, while excessive activation can promote tumor metastasis [105]. Given the systemic toxicity and challenges in controlling the dosage of LPS, current research focuses on developing precise delivery systems for this molecule, aiming to balance its antitumor activity with toxicity risks.
In summary, glycan-based therapeutics offer a unique and biocompatible approach to modulating the TIME. However, their clinical translation faces hurdles, including complex structures, batch-to-batch variability, and for molecules like LPS, the need to balance efficacy with toxicity. The development of advanced delivery systems is therefore crucial to harnessing the full potential of this diverse class of biomolecules.
Fundamentals of hydrogel-based delivery systems
Basic design: composition and crosslinking strategies
Hydrogels are functional materials with a three-dimensional network structure formed by chemical or physical cross-linking of hydrophilic polymers [104]. These systems exhibit high drug loading efficiency, excellent biocompatibility, and responsiveness to stimuli such as pH, temperature, or light. These attributes, combined with a straightforward preparation process, render hydrogels crucial in drug delivery [106]. Based on their composition, they are categorized into three types: natural polymer hydrogels (e.g., chitosan, hyaluronic acid, and sodium alginate), synthetic polymer hydrogels (e.g., poloxamer and polyethylene glycol derivatives), and natural-synthetic hybrid hydrogels [107].
Among various administration routes, injectable hydrogels offer unique spatiotemporal advantages for TIME modulation. They can be injected into specific areas and undergo gelation in situ, offering significant benefits as an invasive yet localized procedure that minimizes trauma and infection risk compared to surgical implantation. The precursor solution gels within the body, adapting to the irregular shapes of tumors and ensuring uniform drug distribution. This ability to conform to the tumor anatomy makes the approach especially suitable for local delivery to deep-seated tumors or for treatments requiring rapid response to dynamic tumor microenvironments [108, 109].
The in situ gelation of injectable hydrogels is achieved through specific crosslinking strategies, which are primarily categorized into physical and chemical crosslinking [110] (Fig. 1). Physical crosslinking relies on non-covalent interactions, such as hydrogen bonds, hydrophobic interactions, or ionic interactions. Taking Poloxamer F127 as an example, hydrogels with thermosensitive properties that exhibit reversible phase transition behavior can be designed based on the polymer’s hydrophobic interactions. It is a low-viscosity solution at low temperatures (< 25 °C) and transitions to a gel state at physiological temperature (about 37 °C) [111, 112]. In addition, ionic interactions and hydrogen bonds are common physical crosslinking mechanisms, employed in systems such as alginate gels crosslinked by divalent cations or DNA-based hydrogels assembled through complementary base pairing [113]. Physical cross-linked hydrogels have the advantages of high biocompatibility and mild, reversible gelation, which makes them suitable for short-term superficial cancer treatment. However, they have defects such as low mechanical strength, poor stability, and uncontrollable degradation processes [114].
Fig. 1.
Physical and chemical crosslinking strategies for constructing hydrogels used in cancer immunotherapy
Chemical cross-linking connects polymer chains through covalent bonds, such as Schiff base reactions, enzyme-catalyzed coupling, or click chemistry reactions, forming a robust cross-linked network that provides higher mechanical strength and stability [115]. For example, hydrogels constructed from chitosan and hyaluronic acid via Schiff base reactions are injectable, gel rapidly, and degrade slowly [116]. Compared to traditional chemical cross-linking, click chemistry and enzyme-catalyzed cross-linking have gained attention due to their mild reaction conditions and lower toxicity of by-products [113, 117]. For example, the tyrosinase-catalyzed system induces oxidation of tyrosine phenolic groups in alginate-tyramine, forming a covalent cross-linked network that significantly enhances the hydrogel’s stability [118]. Chemically cross-linked hydrogels are suitable for long-term sustained release due to their structural stability. However, some chemically cross-linking strategies require the introduction of exogenous cross-linking agents or rely on specific triggering conditions, such as light or enzymes. These conditions may potentially damage the encapsulated active drugs, reducing their efficacy, while the residual cross-linkers or reactive by-products could also raise toxicity concerns. Both click chemistry reactions and enzyme-catalyzed cross-linking have their advantages, and in practical applications, they are often combined to balance injection convenience and therapeutic efficacy.
The core principle: spatiotemporal control of the release window
Critically, the release window serves as the central lever that determines intratumoral exposure profiles, peak/trough cytokine dynamics, therapeutic index, and thus the clinical translatability of hydrogel-based immunotherapy. Hydrogels enable spatiotemporal programmability through local administration with a tunable release window, which is designed to maximize tumor-site exposure while minimizing systemic cytokine spillover. Their multicomponent compatibility facilitates the co-loading of various agents (e.g., chemotherapeutics, photosensitizers, and immune agonists) for synchronized or staged release to achieve synergistic effects. Moreover, stimuli-responsiveness (e.g., to pH, ROS, enzymes, or light) allows for on-demand dosing and peak shaping in response to dynamic tumor microenvironment (TME) features or external cues.
These principles are powerfully illustrated in strategies targeting innate immune pathways such as STING. For instance, the sustained intratumoral release of a STING agonist from a supramolecular hydrogel was shown to reverse immunosuppression and induce potent systemic anti-tumor immunity, highlighting how a prolonged release window can enhance efficacy and reduce systemic toxicity [70]. The synergy between a tunable release window and combination therapy is further demonstrated by systems that co-deliver STING agonists with ROS-generating photosensitizers, where the photodynamic action amplifies STING-mediated immune activation for improved outcomes [71].
Beyond specific immune targets, the fundamental programmability of the release window hinges on advanced material design. The in situ formation of a sustained-release depot can be achieved through innovative strategies such as utilizing the Hofmeister effect to trigger the hydrogelation of non-ionic supramolecular polymers, which demonstrated sustained drug release and potent anticancer activity [119].
System comparison: hydrogels versus nanogels
The selection of an appropriate delivery platform is critical for successful TIME modulation. While injectable hydrogels excel in localized, sustained drug delivery, nanogels—their nanoscale counterparts—offer a distinct set of advantages and challenges, making them suitable for different therapeutic scenarios.
Hydrogels, for instance, can have a relatively slow response time to stimuli such as pH or temperature, and their macroscopic size (usually greater than 100 μm) may limit penetration in dense tumor tissues like those found in pancreatic cancer. This larger size can hinder their ability to penetrate the dense extracellular matrix, potentially affecting the uniform distribution of drugs. Furthermore, drug release from hydrogels is often highly dependent on the diffusion process, which can be a limitation for rapid response applications. In contrast, the nanoscale dimensions of nanogels confer mobility and access that hydrogels lack. This facilitates deep tumor penetration via the enhanced permeability and retention (EPR) effect and, crucially, enables drainage to lymph nodes to initiate systemic immune responses [120–124]. However, this mobility comes at the cost of rapid clearance and reduced local retention, making them less suited for long-term, localized drug exposure compared to hydrogels. Moreover, unmodified nanogels also exhibit rapid drug release, which may cause off-target toxicity [125–127]. Although hydrogels and nanocarriers each have limitations, their stimulus-responsive characteristics provide a rich design foundation for intelligent delivery systems.
A tiered framework for delivery sophistication in TIME modulation
Building on the fundamental design principles of intelligent delivery systems, research in hydrogel-based TIME modulation has evolved along a clear pathway of increasing sophistication, which we summarize as a three-tiered framework (Fig. 2).
Fig. 2.
The three-tiered delivery strategies based on thermosensitive hydrogels for biomacromolecule delivery to modulate TIME
Primary tier: microporous network-mediated drug protection, sustained release, and local enrichment
The widespread application of hydrogels in drug delivery stems largely from their unique internal three-dimensional cross-linked microporous network structure. This structure functions like a highly organized “molecular sponge,” with its primary advantage manifesting in exceptional versatility for drug loading [128]. The enormous specific surface area and internal volume enable the efficient physical entrapment or chemical conjugation of diverse therapeutic molecules, including both hydrophilic/hydrophobic small-molecule drugs and structurally complex, labile biomacromolecules such as proteins, peptides, and nucleic acids [129, 130]. This structural inclusivity provides a robust foundation for delivering multifaceted therapeutic components.
A core function of the microporous network lies in protecting the payload, particularly unstable bioactive macromolecules. The highly hydrated network interior offers a hydrophilic microenvironment akin to the native extracellular matrix. This environment not only minimizes aggregation and denaturation of protein-based drugs but also acts as a physical barrier, partially shielding the cargo from external deleterious factors (e.g., degrading enzymes, free radicals). Consequently, it effectively preserves the structural integrity and bioactivity of the encapsulated drugs, ensuring their intended therapeutic effect at the target site. Furthermore, the entrapped water confers hydrogel mechanical properties and a hydrated surface similar to living soft tissues, endowing them with excellent biocompatibility and significantly reducing risks of foreign body response and immune rejection.
The paramount value of the microporous network resides in its precise control over drug release kinetics. The intricate pore channels inherently form a physical barrier to drug diffusion, significantly prolonging release duration. By meticulously designing the hydrogel’s cross-linking density, polymer composition, porosity, pore size, and distribution, researchers can “tailor” the drug release profile—ranging from rapid release for acute needs, to sustained release over weeks or even months [131, 132]. This spatiotemporal controllability is crucial for maintaining therapeutic concentrations, mitigating initial burst release risks, and improving patient compliance.
Another key advantage of this tier is promoting local drug enrichment. The soft, deformable nature of hydrogels allows them to conform perfectly to irregular tissue surfaces (e.g., post-resection tumor beds), enabling precise localized drug delivery [20, 27, 133–136]. This not only substantially increases drug concentration and residence time at the disease site but also effectively circumvents systemic toxicity associated with whole-body distribution [131, 137].
Upgraded tier: intelligent response-driven delivery – tumor microenvironment triggered precision-controlled release
While injectable hydrogel ensures in situ retention at the injection site (e.g., intratumoral or peritumoral), initial drug release often remains primarily diffusion-dominated, lacking specificity for the TME. Achieving precise controlled release of biomacromolecule drugs (e.g., antibodies, nucleic acids, polypeptides) necessitates integrating TME-specific responsive mechanisms [9, 27, 138, 139]. Smart responsive hydrogels, as a class of three-dimensional network functional material, can dynamically modulate their physicochemical properties in response to internal stimuli (e.g., pH, enzyme, redox potential) or external stimuli (e.g., temperature, light, magnetic field) [107]. They show significant advantages in targeted drug delivery, reducing systemic toxicity, and enhancing treatment efficiency in the field of cancer treatment [140].
Temperature-responsive hydrogels
Temperature-responsive hydrogels undergo phase transitions at specific temperatures, such as the lower critical solution temperature. They typically gel at body temperature (37 °C), thereby facilitating injection and in situ gelation [20, 141–143]. For example, Chen et al. developed a PLGA-PEG-PLGA temperature-responsive hydrogel that is liquid at room temperature and forms a gel after injection into the body at 37 °C. This hydrogel allows for the sustained release of Herceptin for up to 80 days, helping to prevent postoperative recurrence of HER2+ breast cancer [144]. These hydrogels exhibit good injectability and can sustain drug release; however, variations in local temperature may affect the uniformity of their response [145].
pH-responsive hydrogels
The weak acidity (pH 6.5–7.0) of tumor tissue is a typical feature that distinguishes it from the normal physiological environment (pH 7.4) [146–148]. Based on this characteristic, pH-responsive hydrogels induce dynamic changes in their network structure via protonation and deprotonation of ionizable groups, such as carboxyl and amino groups, thereby enabling spatiotemporal controlled drug release and tumor microenvironment-specific responses [114, 115]. Specifically, the pH-triggered gel swelling effect can accelerate drug diffusion [149–151]. For example, in the study by Rajaei et al., the chitosan/alginate/graphene oxide (CS/AG/GO) composite hydrogel loaded with 5-fluorouracil (5-FU) released almost all the drug within 48 h under pH 5.4 conditions, providing an effective solution for breast cancer treatment [152]. pH-responsive hydrogels significantly enhance the accumulation efficiency of highly active biomacromolecules at tumor sites by exhibiting strong targeting ability and rapid responsiveness. They also greatly reduce systemic toxicity caused by nonspecific drug release from normal tissues [153, 154]. However, the inherent pH heterogeneity within tumors can lead to inconsistent drug release profiles. Additionally, the rapid degradation of hydrogels under acidic conditions can intensify burst release, resulting in an excessively fast drug release rate [141, 144, 155].
Enzyme-responsive hydrogels
Specific proteases overexpressed in the TME (e.g., matrix metalloproteinases MMP-2/9, cathepsin B) can also serve as triggers for precise drug release [156–158]. Integrating enzyme substrate peptide sequences (e.g., MMP-cleavable peptide (GKNSVPMSMRGGSNGG-K) as cross-linkers or “molecular switches” into the injectable hydrogel network allows the hydrogel to maintain structural stability and silently carry the drug in normal tissues. Upon encountering elevated protease concentrations in the TME, these sequences are specifically cleaved, causing hydrogel network disintegration or pore enlargement, thereby triggering the rapid release of loaded drugs [159]. This principle is well illustrated by the work of Chen et al., who constructed an MMP-2 responsive hydrogel based on peptide sequences. This hydrogel self-assembled from two peptide chains, Ac-I3SLKG-NH₂ and Ac-I3SLGK-NH₂, where Ac-I3SLKG-NH₂ contains the MMP-2 specific cleavage site SL. In the MMP-2-overexpressing tumor microenvironment, the peptide chains undergo specific cleavage, prompting the hydrogel network to disintegrate and release the encapsulated anticancer peptide G3 for cervical cancer treatment [160]. The enzyme-responsive mechanism offers high enzyme specificity, effectively minimizing drug leakage to off-target tissues. This significantly lowers off-target toxicity and provides important assurance for precise drug intervention in the tumor microenvironment. However, it still faces two optimization issues. First, the drug release rate is significantly affected by enzyme concentration, which varies greatly among individuals. Second, enzyme activity is easily disturbed by fluctuations in the microenvironment, making it difficult to precisely regulate the degradation rate [161].
Redox-responsive hydrogels
Redox-responsive hydrogels utilize the high levels of reactive oxygen species (ROS) and/or glutathione within tumor cells to trigger the cleavage of dynamic bonds such as disulfide bonds, selenide bonds, or phenylboronic esters. This mechanism enables targeted drug release [162]. For example, Wang et al. developed an injectable hydrogel (GEM-STING@Gel) based on polyvinyl alcohol (PVA) and the ROS-cleavable linker TSPBA. This hydrogel is formed through phenylboronic acid-diol crosslinking and undergoes specific degradation in a tumor microenvironment with high levels of ROS. As a result, it achieves controlled release of gemcitabine and STING agonist, DMXAA, which synergistically activate innate immunity and inhibit postoperative recurrence of pancreatic ductal adenocarcinoma [139].
Externally stimulated response and multi-responsive hydrogels
It is worth noting that pH-, enzyme-, and redox-responsive hydrogels achieve targeted drug delivery by responding to tumor microenvironment characteristics. However, these materials are generally limited by tumor heterogeneity and fluctuations in physiological conditions. This common issue may affect the stability of drug release kinetics and indicates the need for further optimization to achieve precise regulation [107, 163].
By utilizing active control methods such as photothermal, ultrasound, or magnetic fields, remote control can be achieved through precise spatial and temporal regulation, promoting the controllable release of hydrogels [164–168]. For example, drug release can be controlled by introducing photosensitive groups that undergo photochemical reactions under specific wavelength illumination [169]. Alternatively, introducing photothermal agents responsive to specific wavelengths can induce tumor ablation or controlled drug release through photothermal conversion [170]. Furthermore, ultrasound, due to its non-invasive nature, precise control, and deep tissue penetration capability, has attracted significant attention in the biomedical field. This renders it an ideal trigger for smart hydrogels, enabling controlled drug release through ultrasound-induced thermal effects or mechanical forces [171, 172]. For instance, Meng et al. developed an ultrasound-responsive composite hydrogel system that can dynamically disrupt the hydrogen bond crosslinking of the gel through ultrasound treatment. This process transforms the gel into a sol state and rapidly releases vaccines. After stopping the ultrasound irradiation, the system can self-heal and restore to a gel state, achieving repeatable on-demand delivery. It supports remote-controlled pulsed release of nano-vaccines and personalized cancer immunotherapy, potentially replacing traditional multiple injection methods for vaccines [173].
Despite advantages such as non-invasiveness, precise spatiotemporal control, and synergistic potential, externally stimulated hydrogels require specialized equipment for operation. Their efficacy can also be influenced by individual anatomical factors (e.g., tissue depth), leading to variable stimulation response efficiency [174]. Therefore, existing research often integrates two or more responsive elements to achieve precise sequential or synergistic drug release. For example, Zhang et al. developed a dual-responsive hydrogel (TOCN/PVA7-PDA@DOX) that integrates pH-sensitivity through carboxyl groups (-COOH) of oxidized cellulose (TOCN-5-NaClO₂) and photothermal-responsiveness via polydopamine (PDA) coating, fabricated via physical crosslinking and rapid PDA encapsulation for synergistic chemo-photothermal therapy in post-operative breast cancer treatment [175]. This multi-responsive hydrogel can enhance drug targeting specificity and reduce off-target effects. It also supports combining multiple therapies and sequentially releasing multiple drugs. However, achieving multi-responsiveness complicates formulation design, requiring a precise balance between different responsive units and making the prediction of drug release and degradation profiles significantly more challenging. Future research should focus on simplifying synthesis, leveraging AI for formulation design, and improving the predictive modeling of release kinetics to enhance clinical translation.
Advanced tier: spatiotemporally programmed delivery mediated by hydrogel-nanoparticle composite systems
Injectable hydrogels encapsulating functionalized nanoparticles (NPs) constitute an advanced hierarchical drug delivery platform. This system significantly enhances spatiotemporally programmed controlled release of biomacromolecule drugs within the TME through multi-level structural design. Its core advantages manifest as a tripartite synergistic mechanism:
Macroscopic Retention & Primary Controlled Release: The injectable hydrogel matrix provides macroscopic in situ retention and a primary controlled-release barrier. It not only ensures prolonged residence of drugs/NPs within the peritumoral area but also precisely regulates NP release kinetics (e.g., sustained release over days to weeks), effectively preventing rapid burst release [176–178].
Nano-Depots & Secondary Precision Release: Encapsulated NPs (e.g., mesoporous silica, liposomes, polymeric micelles) act as nano-scale depots. Surface functionalization with pH-, enzyme-, or redox-responsive elements enables TME-specifically activated secondary precision release (e.g., intracellular release) [9, 179, 180]. Concurrently, the protective microenvironment created by the hydrogel minimizes enzymatic degradation and systemic clearance of biomacromolecule drugs (e.g., siRNA, antibodies) [181].
Multifunctionality Integration: Embedded NPs confer additional functional dimensions, such as enhancing tumor cell uptake via active targeting ligands (e.g., RGD peptides), or integrating photothermal/photodynamic agents and contrast agents for theranostic integration [182–184].
This hierarchical release mechanism, achieved by synergistically regulating diffusion kinetics, hydrogel degradation, and NP-responsive release, enables complex spatiotemporally programmed drug delivery (e.g., sequential “penetration followed by intracellular release,” multi-drug sequential release). For instance, our group developed an innovative tumor microenvironment-adaptive polypeptide composite delivery system, termed Gel/(REG + NG/LY), where REG stands for regorafenib and NG/LY represents the nanogel loaded with the TGF-β inhibitor LY3200882. The thermosensitive hydrogel preferentially releases REG to inhibit tumors and elevate reactive ROS levels. The increased ROS then trigger the ROS-responsive nanogels to release LY3200882. This design enables temporally controlled synergistic therapy by sequentially releasing the drugs, which synchronously inhibited primary tumor growth with a 78.3% inhibition rate, completely eliminated liver metastasis in preclinical models, and reshaped the immune microenvironment by doubling CD8⁺ T cell populations and reducing M2 macrophages by 80% (Fig. 3) [185]. This composite structure can also co-encapsulate free drugs and nanocarrier-loaded drugs, further expanding synergistic therapeutic scenarios [9, 27, 181, 186]. Collectively, these attributes establish the significant clinical translation advantages of nanocomposite hydrogels, providing a revolutionary strategy for the precise tumor delivery of biomacromolecule drugs.
Fig. 3.
The tumor microenvironment-responsive composite nanohydrogel delivery system Gel/(REG + NG/LY) releases Regorafenib (REG) and TGF-β inhibitor (LY3200882) in a time-controlled manner, achieving a triple effect of synergistically inhibiting tumor growth, blocking metastasis, and remodeling the immune microenvironment [185]. Copyright© 2022 Wiley-VCH GmbH
Biomacromolecule-specific delivery strategies assisted by injectable hydrogels
Hydrogel-delivered proteins for TIME engineering
The success of ICB and the challenges encountered in clinical applications have propelled hydrogel systems delivering immune checkpoint inhibitors, such as anti-PD-1 antibodies, to the forefront of TME modulation. Hydrogels that deliver ICB antibodies alone have demonstrated enhanced therapeutic efficacy [187]. However, the therapeutic potential of ICB is constrained by tumor heterogeneity and the immunosuppressive nature of the TME. To address this, hydrogels are increasingly employed for the synergistic delivery of multiple therapeutics, leveraging their spatiotemporal release properties. For instance, combining antibody delivery with ICD-inducing drugs or tumor antigens can synergistically activate immune cells and remodel the TIME, thereby amplifying anti-tumor efficacy [188]. For example, when paired with chemotherapy drugs, this strategy promotes tumor immunogenic death, provides antigens, activates APCs, increases CTL infiltration, and reverses TME suppression [189]. Additionally, hydrogel-assisted delivery enables the simultaneous use of multiple ICB strategies, such as combining anti-CTLA-4 and anti-PD-1 antibodies, to enhance the anti-tumor activity of CD8+ T cells [190]. Beyond direct treatment, post-surgical application of hydrogels containing ICB antibodies at the resection site has proven effective in preventing tumor recurrence [20].
The role of cytokines and chemokines in tumor biology has been extensively studied, with numerous preclinical studies validating their anti-tumor potential. However, the complexity of the TME and the susceptibility of proteins to degradation have limited their clinical translation. Current approaches primarily rely on carriers such as fusion proteins and engineered cells for systemic delivery [191]. Alternatively, they use agonists or antagonists to target cytokine and chemokine pathways for anti-tumor therapy [44, 192]. Nonetheless, systemic administration is associated with significant side effects and off-target effects. Furthermore, many cytokines and chemokines exhibit a “dual role” in tumor progression. Hydrogel-mediated local delivery offers a solution by enabling precise control over dosage and timing. For instance, hydrogels can deliver chemokines through subcutaneous injections to recruit DCs and achieve local immune modulation [193, 194]. Our group developed a thermo-responsive injectable hydrogel (CCL25@gel) that achieves dose- and time-controlled delivery of CCL25 to recruit CCR9+CD8+ T cells into triple-negative breast cancer microenvironment, potently enhancing the therapeutic efficacy of PD-1 blockade immunotherapy [62]. Additionally, combining this strategy with other therapies can yield potent synergistic effects. For example, as shown in Fig. 4, using hydrogels to deliver GM-CSF and Tunicamycin nanoparticles reshaped the tumor microenvironment and significantly enhanced macrophage-mediated tumor cell phagocytosis. When combined with PD-1 antibody, this approach effectively inhibited primary and distant tumors, metastasis, and recurrence [9].
Fig. 4.
(A)The GM-CSF and tunicamycin nanoparticles containing hydrogel mediates reprogramming of the TIME and activates systemic antitumor immunity to inhibit tumor metastasis(B) and recurrence (C) [9]. Copyright © 2023, American Chemical Society
Short peptides, such as anticancer peptides, are not classical biomacromolecules, but they serve dual roles as both hydrogel components and immunomodulators. These peptides integrate material properties with innate immune activation to exert immunomodulatory effects [195, 196]. Recent reviews have extensively elaborated on the mechanisms of peptide hydrogels [197]. Additionally, co-loading tumor neoantigens with vaccine adjuvants in hydrogel platforms facilitates TIME reversal through spatiotemporally coordinated delivery of immunostimulatory signals [198].
Table 1 updates the applications of hydrogels with different material compositions for delivering protein-based molecules in various tumor types and their regulatory mechanisms on the TIME.
Table 1.
Hydrogel-Based delivery of protein molecules for TIME modulation
| Biomacromolecules | Hydrogel materials | Preparation methods | Spatiotemporal release: mechanism design and triggering | Models | In vivo release window | Dosing site | Safety indicators | Key immune outcomes | Ref. | |
|---|---|---|---|---|---|---|---|---|---|---|
| Natural polymer hydrogels | Anti-PD-1 antibody | Sodium alginate | Physical crosslinking | Nano composite system: light and ROS responsive drug release | 4T1breast cancer | - | Intratumoral injection | Normal body weight and H&E staining of major organs | Inducing ICD and enhancing DCs maturation and CD8+ T cell infiltration. Reducing Tregs populations. | [28] |
| Anti-PD-1 antibody | A synthetic peptide containing YSV motif | Physical crosslinking | Intelligent response release: pH-response release | B16F10 melanoma | Sustained release within 168 h vs. free aPD-1(96 h) | Intratumoral injection | Normal body weight | Promoting DCs maturation. Enhancing tumor-infiltrating CD8+ T cells and M1/M2 ratio. | [199] | |
| Anti-PD-1 antibody | Bisphosphonate-modified hyaluronic acid | Physical crosslinking | Diffusion release: sustained local release | Osteosarcoma | Sustained release within 2 weeks | Postoperative cavity | Normal body weight and H&E staining of major organs | Increased CD8+ T-cell activity and CD8+/CD4+ ratio | [133] | |
| Anti-PD-1 antibody | Peptides | Physical crosslinking | Nano composite system: light and Enzyme-responsive release | 4T1 breast cancer | Sustained release over 24 h | Intratumoral injection | Normal body weight and H&E staining of major organs | Activating DCs and CD8+ T cells. | [135] | |
| Anti-PD-1 antibody | Polypeptide | Chemical crosslinking | Diffusion release: sustained local release | B16F10 melanoma | Sustained release over 20 days | Peri-tumor injection | Normal body weight and H&E staining of major organs | Enhancing CD8+ T cell infiltration and reducing Tregs. | [200] | |
| 4-1BB antibody | Oxidized sodium alginate | Chemical crosslinking | Diffusion release: sustained local release | B16F10 melanoma | Sustained release within 8 days | Intratumoral injection | Normal body weight and H&E staining of major organs | Enhancing effector memory T cells for long-term immunity. | [188] | |
| Anti-PD-1 antibody and OX40L | Silk Fibroin | Physical crosslinking | Intelligent response release: thermosensitive response and pH-response release | 4T1, GBM, HCC, PDAC mouse models | 85% cumulative release within 48 h | Intratumoral injection | Normal ALT/AST levels | Improving both the proportion and activation of CD3+CD8+ cytotoxic T cells. | [27] | |
| Anti-PDL1 antibody and CCL25 | β-cyclodextrin-decorated alginate | Physical crosslinking | Diffusion release: sustained local release | B16F10 melanoma | Sustained release of CCL25 over 5 days and peak accumulation of a-PDL1 at 12–24 h | Intratumoral injection | Normal body weight and H&E staining of major organs | Increasing tumor-infiltrating CD8+ T cells. | [194] | |
| Synthetic polymer hydrogels | Cetuximab | PLGA-PEG-PLGA | Physical crosslinking | Intelligent response release: thermosensitive response and sustained release | colorectal cancer. | Completely degraded within 30 days | Peri-tumor injection | Normal H&E staining of major organs | Promoting NK cell infiltration and ADCC activation | [201] |
| GM-CSF | PDLLA-PEG-PDLLA | Physical crosslinking | Intelligent response release: thermosensitive response and sustained release | B16F10 melanoma, CT26 colon carcinoma | Sustained release within 7 days | Subcutaneous injection into the right flank | Normal H&E staining of major organs | Aactivating DCs and enhancing serum TNF-α, IFN-γ, and IL-6 levels | [202] | |
| Anti-PD-1 antibody | mPEG-b-PMet | Physical crosslinking | Intelligent response release: thermosensitive response and ROS-responsive release | B16F10 melanoma | Completely degraded within 10 weeks | Intratumoral injection | Normal body weight and H&E staining of major organs | Inducing ICD and DCs maturation. Enhancing CD8+/CD4+ T cell infiltration and cytokine (IFN-γ, TNF-α, IL-6) levels | [189] | |
| Anti-PD-1 antibody | Pluronic® F127 | Physical crosslinking | Intelligent response release: thermosensitive response and sustained release | 4T1 breast cancer, B16F10 melanoma, GL261 glioblastoma | Sustained release within 11 days | Intratumoral injection | Normal body weight and H&E staining of major organs | Reducing MDSCs/Tregs and enhancing CD8+ T-cell infiltration. | [203] | |
| Anti-CTLA-4 and aPD-1 antibodies | Pluronic® F127,4-arm polyethylene glycol-maleimide | Chemical crosslinking | Diffusion release: sustained local release | 4T1 breast cancer | Release half-life: 3.3 ± 0.4 days | Peri-tumor injection | Normal ALT/AST levels | Enhancing CD8+ T cell-mediated antitumor immunity. | [190] | |
| CCL25 | mPEG-b-PELG | Physical crosslinking | Intelligent response release: thermosensitive response and pH-dependent release | 4T1 breast cancer | Sustained release within 48 h | Intratumoral injection | Normal routine blood parameters and H&E staining of major organs | Recruiting CCR9+CD8+ T cells into tumor microenvironment via CCL25-CCR9 axis. | [62] | |
| Hybrid hydrogels | Anti-OX40 agonist antibody | 4-arm PEG-ONH2, Oxidized dextran | Chemically crosslinked via reaction between 4-arm PEG-ONH2 and ODEX | Diffusion release: sustained local release | E0771 murine breast cancer | 92% cumulative release over 18 days | Postoperative cavity | Normal ALT/AST levels and body weight | Increasing tumor-infiltrating CD8+ T cells and M1 macrophage polarization. | [204] |
| GM-CSF, Catalase (CAT) NPs | Pluronic® F127, Hyaluronic Acid | Physical crosslinking | Nano composite system: thermosensitive and NP-responsive drug release | 4T1 breast cancer | CAT catalytic activity remains stable for up to 6 h | Intratumoral injection | Normal ALT/AST levels, body weight, routine blood parameters and H&E staining of major organs | Activating M1 macrophages and CD8+ T cells. | [9] | |
| Anti-CTLA-4 antibody | Hyaluronic acid and polyethylene glycol diacrylate | Chemical crosslinking | Diffusion release: sustained local release | MC-38 colon cancer | Sustained release within 3 days and AUC ratio of systemic to targeted therapy is 16:1 | Peri-tumor injection | Normal anti-thyroglobulin antibody levels | Increasing CD8+ T cell infiltration. | [187] | |
| Anti-CTLA-4 antibody | Thiolated carboxymethyl hyaluronic acid and polyethylene glycol diacrylate | Physical crosslinking | Diffusion release: sustained local release | MC-38 colon cancer | Rapid release within 24–72 h | Peri-tumor injection | Normal anti-thyroglobulin antibody levels | Reducing Treg suppression and enhancing CD8⁺ T cell cytotoxicity | [205] | |
| Anti-PD-1 antibody | Gelatin methacrylate and methacrylate (MA)-PEG2000 | Chemical crosslinking | Nano composite system: photoactivated and enzyme-responsive drug release | 4T1 breast cancer and LLC | 35% cumulative release within 48 h | Intratumoral injection | Normal body weight and H&E staining of major organs | Increasing CD8+ T/Tregs cell ratio | [206] |
* Given the easy degradation characteristics of biomacromolecules in vivo, and the toxicity considerations during both local and systemic administration, the release window shown in the table refers to the targeted release duration of the delivered biomacromolecules in the body
Hydrogel-delivered nucleic acids for TIME modulation
Hydrogel delivery systems have established well-defined design strategies for nucleic acid-based tumor therapeutics [207], with this review highlighting their unique advantages in TME modulation. Given the susceptibility of nucleic acids to enzymatic degradation, conventional delivery methods typically employ nano-encapsulation followed by incorporation into hydrogel matrices. This dual-protection system improves drug stability and enables targeted, sustained release at the lesions site [208]. The three-dimensional structure of hydrogels allows for the simultaneous loading of multiple functional nucleic acids, such as mRNA and siRNA, enabling spatiotemporally controlled release through smart-responsive mechanisms and synergistic nanoparticle targeting [143]. Table 2 provides an updated overview of hydrogel-mediated nucleic acid delivery in TME regulation. Small molecule nucleic acid drugs, including CpG and cyclic dinucleotides (CDNs), can elicit innate immune response. They can be encapsulated in hydrogels to function as vaccine adjuvants or combined with other therapies to modulate the TME [209–215].
Table 2.
Hydrogel-Based delivery of nucleic acid molecules for TIME modulation
| Biomacromolecules | Hydrogel materials | Preparation methods | Spatiotemporal release: mechanism design and triggering | Models | In vitro release window | Dosing site | Safety indicators | Key immune outcomes | Ref. | |
|---|---|---|---|---|---|---|---|---|---|---|
| Natural polymer hydrogels | Poly(I: C) | Hyaluronic acid | Physical crosslinking | Diffusion release: sustained local release | WEHI 164 sarcoma, bilateral M3-9-M sarcoma and CT26 colon cancer mouse models. | - | Postoperative cavity | - | Recruiting inflammatory monocytes to tdLNs | [225] |
| IRF5 mRNA, CCL5 siRNA | Chitosan, N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride | Physical crosslinking | Nano composite system: thermosensitive and spatiotemporal release | Kras pancreatic cancer | Sustained release over 16 days | Postoperative cavity | Normal body weight and H&E staining of major organs | Increasing M1 macrophage polarization and CD8+ T cell infiltration | [143] | |
| PD-1 DNA aptamer | Rolling Circle Amplification-generated DNA products | Physical crosslinking | Intelligent response release: specific enzymatic cleavage | B16F10 melanoma | Longer time than the free aptamer | Intratumoral injection | - | Enhancing infiltration of CD3+CD4+ and CD3+CD8+ T cells | [226] | |
| PD-L1 SiRNA | Chitosan | Physical crosslinking | Nano composite system: pH-responsive release of NPs | Osteosarcoma | Sustained release over 2 weeks | Postoperative cavity | Normal AST/Cre levels | Increasing CD8+ T cell infiltration and tumor-killing efficacy | [227] | |
| PD-L1 aptamer | DNA | Physical crosslinking | Intelligent response release: light and ROS response | B16F10 melanoma | Cumulative release over 5 days | Postoperative cavity | Normal H&E staining of major organs | Increasing CD8+ T cell infiltration and reducing Tregs | [224] | |
| Synthetic polymer hydrogels | siRad18 | PLGA-PEG-PLGA | Physical crosslinking | Nano composite system: thermosensitive and pH-response release | Osteosarcoma | - | Peri-tumor injection | Normal H&E staining of major organs | Enhancing ICD and DC maturation. | [186] |
| siBACH1 | F127 | Physical crosslinking | Nano composite system: thermosensitive and spatiotemporal release | Esophageal cancer | Sustained release within 72 h | Intratumoral injection | Normal ALT/AST levels and H&E staining of major organs | Increasing CD4+/CD8+T-cell ratios | [181] | |
| Plasmid DNA encoding shRNA871 | PLGA-PEG-PLGA | Physical crosslinking | Intelligent response release: thermosensitive response and sustained release | U87MG Glioblastoma | 60% cumulative release within 2 days | Postoperative cavity | Normal anti-thyroglobulin antibody levels | Downregulating CD47 protein. Increasing macrophage infiltration and enhancing macrophage phagocytosis | [228] | |
| mRNA (mOVA) | Polyethylenimine and Graphene oxide | Physical crosslinking | Nano composite system: spatiotemporal release | B16-OVA melanoma | Sustained release over 30 days | Subcutaneous injection | Normal H&E staining of major organs | Increasing CD8+ T cell infiltration | [229] | |
| Hybrid hydrogels | siSTAT3 siRNA and Bim mRNA | Methacrylated gelatin | Chemical crosslinking | Intelligent response release: Photosensitive and enzyme-responsive drug release | C26 colon cancer | Completely degraded within 7 days | Peri-tumor injection | Normal H&E staining of major organs | Recruiting DCs and promotes their maturation and increasing CD4+/CD8+ T-cell ratio in tumors | [208] |
* Given the easy degradation characteristics of biomacromolecules in vivo, and the toxicity considerations during both local and systemic administration, the release window shown in the table refers to the targeted release duration of the delivered biomacromolecules in the body
DNA, a naturally occurring material, has been extensively explored for hydrogel fabrication, as detailed in existing reviews [216, 217]. Recent studies demonstrate that functional nucleic acid components, such as aptamers, siRNA, and CpG oligonucleotides, can be directly integrated into DNA hydrogel frameworks. This integration facilitates controlled therapeutic release during matrix degradation, enabling precise regulation of the immune microenvironment [218–221]. For example, Makiya et al. developed a CpG-containing DNA hydrogel to deliver chemotherapy drugs, inducing tumor ICD while simultaneously activating DCs [222]. Yang et al. designed and synthesized nucleic acid macromolecules with immune-functional units (e.g., CpG) as hydrogel materials. These hydrogels encapsulate restriction endonuclease nanoparticles and release them responsively in the TME, decomposing into immune-functional units that reshape the TIME [223]. In another research, Wang et al. designed a photosensitive DNA hydrogel integrating PD-L1 aptamers and CpG oligonucleotides. This hydrogel activates DCs through photodynamic therapy, enhances CD8+ T cell infiltration, and remodels the TIME [224]. Collectively, these innovative designs underscore the technical superiority of DNA hydrogels in achieving dual-dimensional spatiotemporal regulation.
Hydrogel-delivered glycans for TIME reprogramming
Polysaccharide materials can be fundamental components of hydrogels, primarily serving as functional carriers for therapeutic molecules in co-delivery systems due to their inherent immunomodulatory properties. As discussions on polysaccharide-based hydrogels have been thoroughly covered in existing reviews, they will not be reiterated here.
LPS represents another class of glycan molecules with immunomodulatory functions. As a classical TLR4 agonist [230], LPS exhibits unique capabilities in activating M1 macrophage and inducing systemic immune-inflammatory responses. Although LPS has the potential to reverse immunosuppressive states by remodelling the TME [231], its clinical application is limited by a dose-dependent paradox. High-dose systemic administration can lead to severe toxicity [232], while low-dose regimens often fail to achieve therapeutic levels at tumor sites [233]. The macromolecular nature of LPS imposes stringent requirements on delivery vehicles. Hydrogel systems emerge as innovative solutions due to their three-dimensional porous network structure and spatiotemporally controlled release properties. Notably, Shi et al. demonstrated that hydrogel-mediated co-delivery of LPS with anti-angiogenic peptides synergistically enhances IFN-γ/IL-4 secretion, achieving significant tumor suppression in Lewis lung carcinoma models [234]. In Fig. 5, our research group developed a thermosensitive hydrogel system composed of F127, carboxymethyl chitosan, and glyoxal to assist peritumoral delivery of LPS. This localized delivery strategie successfully remodels the TIME, evidenced by DCs activation, TAMs phenotype reprogramming, and enhanced CD8+ T cell-mediated antitumor immunity, ultimately potentiating ICB efficacy [235].
Fig. 5.
(A) Peritumoral injection of GelF127CS-LPS in combination with anti-PD-1 treatment successfully remodel the TIME. (B) When delivered through GelF127CS, LPS accumulates locally within the tumor tissue. (C) The strategy lead to the activation of DCs, phenotypic reprogramming of TAMs, and enhancement of CD8+ T cell-mediated antitumor immunity [235]. Copyright © 2025 Acta Materialia Inc. Published by Elsevier Inc
Multicomponent synergistic delivery systems
The complexity of the TIME necessitates delivery systems capable of orchestrating the spatiotemporal action patterns of multiple therapeutic components. To address this challenge, researchers are leveraging the high loading capacity and controllable release properties of hydrogels to develop diverse synergistic delivery strategies.
The primary strategy focuses on regulating the spatial distribution of molecules, often achieved through nanocarrier co-loading technology. Encapsulating functionally distinct molecules (e.g., chemotherapeutic agents and immunomodulators) together or separately within NPs, followed by embedding within a hydrogel matrix, enables precise guidance of their localization within tumor tissue, achieving spatial synergistic enhancement [236].
A second critical approach exploits the inherent metabolic differences between biomacromolecules to achieve temporally programmed release. For example, the CCL21a/ExoGM−CSF+Ce6@nanoGel system ingeniously exploits the temporal action differences between a chemokine and mRNA: The hydrogel first releases CCL21a, directionally recruiting metastatic cancer cells from tumor-draining lymph nodes to the implantation site. Subsequently, these recruited cells are eliminated in situ by photodynamic therapy (PDT) mediated by the co-delivered photosensitizer Ce6, providing tumor antigens. Finally, GM-CSF mRNA encapsulated within exosomes is translated, releasing GM-CSF to recruit and activate DCs, driving a sustained “recruit-eliminate-activate” sequential antitumor immune response (Fig. 6) [25].
Fig. 6.
(A) Hydrogels simultaneously deliver chemokines and mRNA to regulate the tumor TIME. (B) The schematic of the hydrogel formation and the release profile of CCL21a from different hydrogels. (C) The CCL21a/ExoGM-CSF + Ce6@nanoGel combined with ultrasound strategy promotes the maturation of DCs [25]. Copyright © 2023 The Authors. Advanced Science published by Wiley-VCH GmbH
The third core strategy focuses on stimulus-responsive synergistic release, employing environmentally responsive materials within hydrogels that sense specific TME signals (e.g., pH, ROS, specific enzymes) [28, 135, 237]. This approach is particularly effective in scenarios requiring the simultaneous release of critical components, such as the co-delivery of antigens (proteins) and nucleic acid adjuvants (e.g., Poly(I: C)). The sustained release properties of hydrogels enable the concurrent activation of both local and systemic immune responses [238]. Of particular interest are DNA hydrogel systems that incorporate functional nucleic acid elements (e.g., CpG) [239]. During their degradation, these systems facilitate the spatiotemporally coordinated and synchronous release of nucleic acid-based immune activators (e.g., CpG) and encapsulated protein therapeutics (e.g., antibodies), significantly enhancing TIME modulation through the synergistic effects of this dual release mechanism.
Table 3 summarizes representative studies in recent years that have successfully achieved the synergistic delivery of various types of biomacromolecules (proteins, nucleic acids, and glycans). These advanced spatiotemporal control strategies, by precisely coordinating the location, timing, and mode of action of different molecules, provide powerful and flexible tools to address the complexity of the TIME and enhance the effectiveness of immunotherapy.
Table 3.
Hydrogel-Based delivery of multicomponent molecules for TIME modulation
| Biomacromolecules | Hydrogel materials | Preparation methods | Spatiotemporal release: mechanism design and triggering | Models | In vitro release window | Dosing site | Safety indicators | Key immune outcomes | Ref. | |
|---|---|---|---|---|---|---|---|---|---|---|
| Natural polymer hydrogels | Neoantigen peptides, Poly(I: C), Thymosin α−1 | Hyaluronic acid | Physical Crosslinking | Diffusion release: sustained local release | E0771 Breast Cancer, LLC Lung CancerMC38 Colon Cancer | - | Subcutaneous injection | Normal ALT/AST levels and H&E staining of major organs | Enhancing neoantigen-specific CD8+ T cell infiltration.Suppressing Tregs and activated CD8+CD69+ T cells.Inducing long-term immune memory | [240] |
| Antigenic peptides (OVA/MG7), CpG-ODN | RADA32 peptide (self-assembling peptide), Mn2+ | Physical Crosslinking | Nano composite system: thermosensitive and spatiotemporal release | C57 mouse gastric cancer model (YDN16 cells) | Sustained release over 7 days | Subcutaneous injection | - | Enhancing DC maturation and antigen presentation and long-lasting antitumor immunity | [236] | |
| siIDO1 and CXCL10 | Self-assembling oligopeptide hydrogel | Physical Crosslinking | Nano composite system: thermosensitive and NP-responsive drug release | GL261 glioma | CXCL10 released 89.23 ± 4.37% and siIDO1 released 75.23 ± 10.41% over 12 days | Postoperative cavity | Normal body weight | Activating DCs and increasing CD8+ T/Treg ratio | [26] | |
| Nps encapsulating CAR plasmids targeting CD133 anti-CD47 antibody | Peptides | Physical Crosslinking | Diffusion release: sustained local release | GL261 glioma model and orthotopic patient-derived glioblastoma humanized mouse model | Retained more than 5 days | Postoperative cavity | Normal body weight and H&E staining of major organs | Reprogramming macrophage: CAR-Ms polarized to M1 phenotype. Enhancing CD8+ T cell infiltration. | [241] | |
| Synthetic polymer hydrogels | CCL21a (chemokine), GM-CSF mRNA | Gelatin methacryloyl | Physical Crosslinking | Nano composite system: spatiotemporally programmed release | CT26 colon cancer and 4T1 breast cancer | CCL21a is released early, and GM-CSF mRNA is released after 24 h. | Peri-tumor injection | Normal H&E staining of major organs | Inducing immunogenic cell death and activating dendritic cells and CD8+ T cells. | [25] |
| Antigen (OVA) and CpG-ODN | Poly(ε-caprolactone-co-glycolide)-b-PEG-b-poly(ε-caprolactone-co-glycolide) | Physical Crosslinking | Intelligent response release: thermosensitive response and sustained release | E.G7-OVA lymphoma | Completely degraded within 10 days | Subcutaneous injection | - | Enhancing DC maturation and inducing tumor-specific CD8+ T cell responses. | [242] | |
| Hybrid hydrogels | OVA-expressing plasmid, GM-CSF | Poly(ε-caprolactone-co-lactide) (PCLA)-functionalized hyaluronic acid | Physical crosslinking and chemical crosslinking | Diffusion release: sustained local release | B16/OVA melanoma | Sustained release over 10 days | Subcutaneous injection | - | Increasing DCs polarization and robusting CD4+ T cell activation | [243] |
| Chemokine MIP3α and IL10 siRNA and DNA antigen (MCP3sFv20) | Vinyl sulfone-modified dextran and tetra-thiolated polyethylene glycol | Chemical crosslinking | Nano composite system: spatiotemporal release | A20 B-cell lymphoma | MIP3α is released over 3 days | Intramuscular injection | - | Increasing DCs recruitment and promoting DCs maturation. Activating CTL cells. | [244] |
* Given the easy degradation characteristics of biomacromolecules in vivo, and the toxicity considerations during both local and systemic administration, the release window shown in the table refers to the targeted release duration of the delivered biomacromolecules in the body
Challenges and future outlook
Hydrogel delivery systems, leveraging in situ gelation technology for local administration, successfully circumvent bottlenecks associated with traditional intravenous injection—such as systemic toxicity, off-target effects, and low tumor accumulation—offering unique advantages for the precise modulation of the TIME by biomacromolecules. Despite this significant potential demonstrated in preclinical studies, the clinical translation of hydrogels for active tumor immunotherapy remains in its infancy.
Current clinical status of hydrogels in oncology
Hydrogels have garnered diverse applications in clinical oncology, primarily in supportive and adjunctive roles. These can be categorized into three main scenarios: as topical medications for managing radiotherapy- or chemotherapy-induced dermatitis [245, 246]; as local filling or implant materials to promote healing and prevent adhesions in postoperative wound sites [247]; and as injectable spacers to protect non-target organs during radiotherapy or to assist in endoscopic procedures [248–250].
However, the clinical translation of hydrogels as platforms for active tumor treatment, particularly for precision modulation of the TIME, remains significantly limited. Only a few products exemplify this advanced therapeutic approach. A landmark case is JELMYTO®, an FDA-approved thermosensitive hydrogel that delivers mitomycin for the treatment of low-grade upper urinary tract urothelial carcinoma by providing sustained local chemotherapy [251–253]. This thermosensitive hydrogel contains mitomycin and, after being infused into the bladder via the urethra, uses its temperature-sensitive properties to gel in place within the bladder. This gelation prolongs the release time of mitomycin, provides sustained drug delivery, reduces the frequency of administration, and ultimately achieves a therapeutic effect against tumors. Notably, the field is now evolving towards immunotherapy. A recently registered clinical trial (NCT04062721) aims to evaluate an injectable hydrogel loaded with immune agonists (mifamurtide and GM-CSF) to enhance local immune responses following tumor ablation in colorectal liver metastases [254]. This trial marks a critical step toward harnessing hydrogels for active immunomodulation in cancer therapy.
The translation of hydrogel-based platforms for sophisticated tumor immunotherapy faces several key challenges:
The first challenge is the complexity of drug synergy mechanisms and carrier design. Current research exhibits insufficient analysis of the synergistic mechanisms underlying co-delivered biomacromolecules and often overlooks dynamic changes in drug degradation kinetics and PK. While multi-drug combinations can overcome TIME heterogeneity, the quantitative control of drug action timing, release profile differences, and carrier compatibility still lacks systematic methods, severely hindering synergy research and clinical translation [255].
The second challenge lies in the inefficiency of formulation optimization and limitations of evaluation systems. Optimizing hydrogel parameters (e.g., pore structure, crosslinking density) relies heavily on trial-and-error approaches, making it difficult to meet the demands of high-throughput screening for biomacromolecule drug combinations [17]. Furthermore, current evaluation systems struggle to recapitulate the physiological complexity of the in vivo TME: In vitro models lack immune microenvironment interactions, while animal models suffer from interspecies disparities, limiting the precise analysis of spatiotemporal drug release control and immunomodulatory mechanisms [256, 257].
To address these issues, future research needs to focus on two key interdisciplinary technological directions.
AI-assisted hydrogel design and biomacromolecules co-delivery
Artificial intelligence, a powerful tool that employs algorithms to parse complex data and simulate intelligent decision-making, is profoundly transforming the biomedical field [258]. In developing injectable hydrogel delivery systems to modulate the tumor immune microenvironment, AI technology demonstrates potential to systematically overcome the efficiency limitations of traditional trial-and-error approaches [259]. By constructing multidimensional models encompassing material properties, drug release profiles, and therapeutic efficacy predictions, AI can precisely simulate interactions between hydrogel physicochemical characteristics (e.g., degradation kinetics, drug diffusion coefficients) and biomacromolecules, enabling efficient prediction and optimization of controlled release behaviours. Existing research has preliminarily validated this potential: machine learning-based peptide hydrogel databases can predict material gelation capabilities [260], while expanding multi-material databases and utilizing AI algorithms for customized design will further significantly enhance optimization efficiency [261]. Current advancements include AI-constructed models predicting hydrogel drug release kinetics [262, 263], and the integration of image recognition technologies for real-time monitoring of release processes to dynamically adjust parameters [259, 264, 265]. These innovations not only substantially improve design accuracy and shorten R&D cycles but also markedly reduce reliance on animal testing, achieving dual advancements in research efficiency and ethical standards.
Due to the high heterogeneity of the TME, single-drug interventions often prove inadequate. AI exhibits unique value in orchestrating the co-delivery of biomacromolecules with diverse mechanisms (e.g., immune checkpoint inhibitors combined with innate immune agonists). Its core capability lies in integrating multiscale data: by synthesizing TME omics data, immune pathway knowledge graphs, and molecular mechanisms of action, AI leverages graph neural networks to quantitatively analyse synergistic/antagonistic effects between molecules (Fig. 7 (B)) [266–268]. Furthermore, through multi-objective optimization models, AI can precisely coordinate differential release rates of distinct molecules from the same hydrogel, temporal synergy windows (e.g., “suppression relief prior to immune activation”), and spatial distribution requirements. Crucially, it can autonomously optimize key parameters—including polymer selection, crosslinking density, and molecular loading ratios—using reinforcement learning or evolutionary algorithms, driving hydrogels toward achieving optimal synergistic controlled release of multiple biomacromolecules [269, 270]. In Fig. 7 (A), Xu et al. [271] used dynamic regression and latent variable modelling for data fitting. Through numerical optimization, they have ultimately selected the optimal hydrogel formulation characterized by low burst release, high total release amount, controllable release rate, and high transparency. This approach provides an efficient design platform for developing protein delivery systems. Future developments will see enhanced simulation of drug release profiles and improved accuracy in predicting in vivo efficacy, positioning AI as the central driving force in creating next-generation intelligent delivery platforms for immunotherapy. This promises revolutionary tools to overcome the complexity of the TME.
Fig. 7.
(A) High-throughput synthesis and optimization of injectable hydrazone-crosslinked hydrogels for tunable protein delivery [271]. Copyright © 2020, American Chemical Society. (B) The novel deep learning model DGSSynADR predicts anticancer synergistic drug combinations based on the overall structural features of drugs and proteins [266]. Copyright © The Author(s) 2023. Published by Oxford University Press
Guiding hydrogel drug release optimization: strategic selection of in vitro and in vivo evaluation models
Regarding evaluation systems, considering animal welfare and the heterogeneity of the human tumor microenvironment, organoids have become an effective approach for in vitro drug screening. Organoids are three-dimensional structures with self-organizing properties derived from primary tissues (Fig. 8A). They can not only reproduce the key histological features and the potential for multi-lineage differentiation of the source tissue but also have the advantage of a short culture cycle. In addition, organoid technology allows for the simultaneous generation of normal tissue organoids as controls, thereby providing a reliable experimental [256]. Currently, AI algorithms have been developed and applied to organoid construction and high-throughput multi-omics data analysis [272–274]. In the future, this technology can be further integrated to establish a biopharmaceutical database for high-throughput screening of various drug combination delivery strategies [275].
Fig. 8.
(A) The generation of patient-derived organoids which accurately replicate the histopathological features, genetic profiles, mutational landscapes, and therapeutic responses of the original tumors [281]. Copyright © The Author(s) 2022. (B) Generation of hu-mice with a functional human immune system and autologous leukemia [278]. Copyright © 2016 The Author(s). Published by Elsevier B.V
Because of the complexity of human immune system homeostasis and the tumor microenvironment [257], mechanistic studies of organoids in vitro lack the physiological complexity associated with in vivo systems [276]. Therefore, there are certain limitations in studying the mechanisms of changes in immune cell phenotypes and functions after anticancer treatment with drug delivery systems. Humanized animals serve as essential tools to analyze the human tumor immune microenvironment, compensating the limitations of organoids. “Tumor-Immune System” Dual-Humanized Mice are immunodeficient mice co-transplanted with key components of the human tumor and immune system. They can be used for real-time in vivo studies of human immune function under both physiological and pathological conditions [277]. For example, Yang et al. simulated the occurrence and development of human B-cell acute lymphoblastic leukaemia in humanized mice with an intact immune system by transplanting human fetal thymus tissue and MLL-AF9-transduced CD34+ hematopoietic stem cells (Fig. 8B) [278]. In solid tumors, Yang et al. constructed a humanized mouse model capable of the large-scale generation of functional tumor antigen-specific T cells. This was achieved by transducing human CD34+ hematopoietic stem cells with a lentivirus carrying the MART-1-specific TCR gene and co-transplanting these transduced cells with human fetal thymic tissue into NSG mice. This model was used to improve melanoma therapy by enhancing the efficacy of CAR-T cell treatment [279]. Humanized mice with functional human immune systems are a powerful model for understanding interactions between human immune components and cancers. They also promote the development of anticancer interventions [280], and will benefit therapeutic hydrogel evaluations.
Conclusion
In summary, injectable hydrogels have emerged as intelligent delivery platforms for biomacromolecules, including proteins, nucleic acids, and glycans, by enabling precise spatiotemporal control through three levels of functionality: microporous structural networks, stimuli-responsive mechanisms, and nanoparticle-hydrogel composite systems. These systems not only protect sensitive biological agents from degradation but also minimize systemic toxicity and effectively reprogram the tumor immune microenvironment, offering a promising path forward for precision cancer immunotherapy.
To bridge the gap between laboratory innovation and clinical application, future progress will rely heavily on interdisciplinary integration across computational, material, and biological sciences. Notably, the convergence of AI-driven hydrogel design, nanoscale delivery engineering, and next-generation evaluation platforms, such as patient-derived organoids and humanized animal models, will be essential to accelerating the discovery-validation-translation cycle. AI can serve as a central orchestrator by predicting optimal formulations, modeling synergistic release profiles, and simulating immune responses under different microenvironmental conditions.
Such a holistic framework will enable the rational design of personalized, programmable immunotherapeutic systems, capable of adapting to the complex heterogeneity of individual tumors. Ultimately, these efforts hold significant potential to transform nano-enabled biomacromolecule delivery systems from experimental constructs into clinically translatable tools for on-demand, site-specific, and immune-tailored cancer therapy.
Abbreviations
- TIME
Tumor immune microenvironment
- ICB
Immune checkpoint blockade
- DCs
Dendritic cells
- CTLs
Cytotoxic T lymphocytes
- CSF1R
Colony stimulating factor 1 receptor
- STING
Stimulator of interferon genes
- GM-CSF
Granulocyte macrophage-colony stimulating factor
- PD-L1
Programmed cell death ligand 1
- CRS
Cytokine release syndrome
- ICD
Immunogenic cell death
- ADCs
Antibody-drug conjugates
- TLR
Toll-like receptor
- Tregs
Regulatory T cells
- MDSCs
Myeloid-derived suppressor cells
- TAMs
Tumor-associated macrophages
- irAEs
Immune-related adverse events
- mRNA
Messenger RNA
- siRNA
Small interfering RNA
- pDNA
Plasmid DNA
- miRNA
microRNA
- CAR
Chimeric antigen receptor
- TAAs
Tumor-associated antigens
- PRRs
Pattern recognition receptors
- CAR-T
Chimeric antigen receptor T cells
- ASO
Antisense Oligonucleotides
- LPS
Lipopolysaccharides
- EPR
Enhanced permeability and retention
- MPS
Mononuclear phagocyte system
- PAMP
Pathogen-associated molecular pattern
- TNF
Tumor necrosis factor
- EMT
Epithelial mesenchymal transition
- ROS
Reactive oxygen species
- TME
Tumor microenvironment
- CDNs
Cyclic dinucleotides
- PDT
Photodynamic therapy
- AI
Artificial intelligence
Author contributions
H.Z. investigation, writing-original draft, formal analysis. H.Z. investigation, software. W. Y. writing-original draft, H.S. investigation, software. Y.Y. review & editing, supervision. Z.L. review & editing, supervision. D.S. review & editing, supervision, conceptualization. Y.Z. review & editing, supervision, conceptualization, funding acquisition. T.S. review & editing, supervision, conceptualization, funding acquisition.
Funding
This research was supported by National Key Research and Development Program of China, grant number, 2024YFA0918600; the Natural Science Foundation of China, grant number, 82325029, 32171379, 82472123, U22A20156, W2441022; the Natural Science Foundation of Jilin Province, grant number, YDZJ202401272ZYTS; the Bethune Medical Department of Jilin University, grant number, 2022JBGS01; Jilin University First Hospital and Academician Chen Xuesi’s Team Joint Laboratory Interdisciplinary Project, grant number, 2022YYGFZJC006; Open Project of Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, grant number, KFKTZD2206; the Fundamental Research Funds for the Central Universities, JLU, the Bethune Plan Project of Jilin University, grant number, 2024B03.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
All authors have provided consent for the manuscript to be published in Journal of Nanobiotechnology.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Hongxu Zhou and Hao Zheng contributed equally to the manuscript.
Contributor Information
Zhuo Li, Email: zhuoli@jlu.edu.cn.
Dong Song, Email: songdong@jlu.edu.cn.
Yuning Zhang, Email: zhangyuning@jlu.edu.cn.
Tianmeng Sun, Email: tsun41@jlu.edu.cn.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.