3.1 Design Strategies of pH-Responsive Hydrogels

pH-responsive hydrogels are engineered through the incorporation of pH-sensitive linkages that undergo targeted structural transformations or cleavage in specific pH environments, enabling spatiotemporally controlled drug release. Primary design strategies involve integrating acid-labile covalent bonds (e.g., imine bonds and boronate esters) or ionizable moieties (e.g., citraconic anhydride and dimethylmaleic anhydride) into the polymer network [62, 63]. Among them, Schiff base linkages, including imines, hydrazones, and oximes, are widely employed due to their sensitivity to mildly acidic conditions. These dynamic covalent bonds form via condensation reactions between primary amines and carbonyl compounds (aldehydes/ketones), generating hydrolytically labile imine bonds (C = N) [64]. Under acidic conditions, these linkages undergo rapid hydrolysis, leading to network disintegration and therapeutic release, yet remain stable at physiological pH to preserve hydrogel's structural integrity. In addition to covalent systems, non-covalently cross-linked hydrogels can also achieve pH responsiveness. For example, pH-labile hydrogen bonds, characterized by weak, reversible interactions, undergo dissociation upon protonation of polymeric chains in acidic microenvironments, thereby facilitating on-demand drug release [65].

3.2 Design Strategies of ROS-Responsive Hydrogels

ROS-responsive hydrogels are designed by incorporating redox-sensitive motifs that undergo structural or chemical transformation upon ROS exposure. These systems often integrate ROS-labile linkages through covalent, coordination, or supramolecular interactions [66]. The selection of ROS-sensitive functional groups and their integration into polymeric frameworks plays a pivotal role in tuning both responsiveness and stability. A widely employed class involves phenylboronic acid esters (PBAEs), which are oxidized by ROS to yield hydrophilic phenols and boric acid. This transformation not only weakens the hydrophobic interactions within the hydrogel matrix, promoting swelling and drug diffusion, but also confers intrinsic ROS-scavenging capability [67]. An alternative design strategy involves utilizing sulfur-based functionalities, including thioacetals, thioketals, and thioethers [68]. Among these, thioketal linkages, synthesized via the condensation of ketones and dithiols, maintain stability under physiological conditions but undergo selective C-S bond cleavage when exposed to hydrogen peroxide or hydroxyl radicals. This irreversible cleavage mechanism enables precise spatiotemporal hydrogel degradation [69].

Moreover, redox-active natural amino acids can be incorporated into hydrogel matrices to impart ROS sensitivity. Disulfide bonds (-S-S-), formed through oxidative coupling of cysteine residues, constitute redox-switchable units that facilitate network disassembly in ROS-rich microenvironments [70, 71]. These bonds undergo stepwise oxidation to generate a series of sulfur-containing intermediates, ultimately facilitating the controlled disassembly of hydrogel [72]. In addition to cleavage-based strategies, ROS-responsive systems can also be constructed using bioinspired oxidative conversion pathways. For example, l-Arginine, a precursor of nitric oxide (NO), undergoes nonenzymatic oxidation by hydrogen peroxide to generate NO in situ, providing a biomimetic route for spatiotemporally controlled NO release [73].

3.3 Design Strategies for Glucose-Responsive Hydrogels

Glucose, the primary metabolic substrate for most tissues, is tightly regulated under physiological conditions. However, pathological hyperglycemia elevates glucose concentrations to levels markedly exceeding the norm, disrupting metabolic homeostasis [74, 75]. Capitalizing on this dysregulation, glucose-responsive hydrogels have been developed by incorporating glucose-sensitive components, including natural proteins (glucose oxidase (GOx) and concanavalin A (ConA)), and synthetic moieties like phenylboronic acid (PBA). GOx is a flavin-containing glycoprotein that catalyzes the oxidation of glucose into gluconic acid and hydrogen peroxide [76]. This enzymatic reaction is highly dependent on glucose concentration, thereby inducing alterations in key physicochemical hydrogel properties, including swelling kinetics, degradation profiles, and mechanical integrity. ConA, a plant-derived lectin with affinity for α-d-glucose and α-d-mannose, enables reversible noncovalent crosslinking with glycosylated polymers, facilitating glucose-responsive network assembly and disassembly [77]. Conversely, PBA serves as a synthetic glucose-recognition unit, capable of forming reversible covalent bonds with cis-diols through dynamic boronate esterification. PBA exists in equilibrium between a neutral trigonal configuration and an anionic tetrahedral boronate form, with the latter demonstrating enhanced glucose-binding affinity. Under hyperglycemic conditions, cyclic boronate ester formation modulates hydrogel properties, altering crosslinking density, swelling behavior, and inducing sol-gel transitions [78, 79]. This modular design allows for precise glucose-triggered drug release without reliance on biological components.

3.4 Design Strategies for MMPs-Responsive Hydrogels

Enzyme-responsive hydrogels leverage the high substrate selectivity and catalytic efficiency of specific enzymes to achieve controlled matrix remodeling or drug release. Among these systems, MMPs-responsive platforms have garnered attention due to their well-characterized substrate specificity and tunable enzymatic activity. MMPs serve as biologically programmable triggers capable of initiating hydrogel degradation or payload liberation with spatiotemporal precision [80]. MMP-responsive hydrogel design typically follows two complementary strategies. Molecular engineering incorporates enzyme-cleavable peptide sequences into polymer networks via physical adsorption or covalent conjugation. These peptides undergo site-specific cleavage upon MMP exposure, enabling programmable hydrogel degradation and controlled therapeutic release [81]. Another alternative and synergistic design leverages gelatin that inherently retains MMP-sensitive domains. When formulated as hydrogel matrices or micro/nanoparticulate carriers, gelatin undergoes enzymatic degradation upon MMP recognition. This process modifies network porosity and triggers matrix disassembly, ultimately facilitating targeted drug delivery [82-84].

4.1 Ameliorate the Hyperglycemia Microenvironment

The hyperglycemic microenvironment impedes normal tissue repair by promoting advanced glycation end-product (AGE) formation, impairing immune responses, inducing oxidative stress, and suppressing angiogenesis [85]. Consequently, modulating local glucose levels at diabetic wounds using glucose-responsive hydrogels is critical. Most current glucose-responsive hydrogels employ GOx as the sensing mechanism. GOx catalyzes glucose oxidation, generating gluconic acid and H₂O₂, thereby simultaneously depleting local glucose and creating an acidic microenvironment that triggers drug release [86-93]. Beyond glucose depletion, controlled insulin release is essential. Insulin not only regulates glycemia, mitigating hyperglycemia-induced inflammation and oxidative stress, but also directly promotes collagen synthesis and angiogenesis, key processes for wound closure and regeneration. To achieve this, diverse hydrogel designs have been developed. For example, our group developed a hybrid hydrogel (PPIC) based on a PEG-DA matrix integrated with gallic acid (GA)-grafted chitosan (CS). Insulin nanoparticles (NPs) were encapsulated within PBA-modified polyethylenimine (PEI) network. Glucose binding to PBA triggered controlled insulin release, while the polyphenol backbone provided ROS-scavenging activity. This dual-function system improved glucose regulation, enhanced collagen deposition, and accelerated diabetic wound closure in vivo (Figure 3A) [94]. Additionally, to address limitations in response speed and spatial precision, microneedle (MN)-based glucose-responsive systems have emerged. Xue et al. fabricated an insulin-loaded hydrogel MN (Gel-AFPBA-ins MN) using gelatin methacryloyl (GelMA), the glucose-responsive monomer 4-(2-acrylamidoethylcarbamoyl)−3-fluorophenylboronic acid (AFPBA), and glucose-conjugated insulin (G-insulin). Under hyperglycemia, glucose binding to anionic boronates increased osmotic pressure, inducing matrix swelling and facilitating insulin release. In vivo studies confirmed enhanced collagen deposition and improved healing in diabetic wounds using this MN patch [96].

4.2 Modulate Inflammatory Response

The complex interplay of immune cells during inflammation necessitates precise therapeutic modulation. Responsive hydrogels offer targeted strategies to regulate immune/inflammatory responses through controlled drug release triggered by specific wound microenvironment cues [97-99]. For instance, pH-responsive hydrogels leverage acidic microenvironments to trigger controlled drug release that modulates macrophage polarization. Xuan et al. developed a chitosan hydrogel modified with 4-formylphenylboronic acid (FPBA) to load formyl-methyl-leucine-phenylalanine (fMLP) and SiO₂-FasL. Acidification (pH ~5.5) cleaved Schiff base bonds, releasing SiO₂-FasL to induce neutrophil apoptosis and promote M2 macrophage polarization, accelerating healing [100]. Similarly, Cai et al. synthesized an HA-collagen hydrogel crosslinked via hydrazone bonds, rapidly gelling under neutral/alkaline conditions. In acidic DFU environments, bond cleavage triggered metformin release, enhancing fibroblast proliferation and macrophage modulation [101]. For ROS-responsive strategies, Liu et al. engineered a composite hydrogel (TPA-PVA) using a ROS-cleavable TPA crosslinker. Elevated ROS levels degraded the linker, enabling spatiotemporal release of mupirocin and GM-CSF. This controlled delivery modulated the immune microenvironment and promoted angiogenesis (Figure 3B) [95]. Guo et al. utilized a 3D-printed hydrogel incorporating a ROS-degradable polyurethane (PFKU) membrane loaded with doxycycline hydrochloride (DOXH). The thioketal bonds in PFKU undergo cleavage under high ROS conditions, facilitating sustained DOXH release that stimulated endothelial migration and M2 macrophage polarization, significantly improving wound repair in diabetic mice [102]. Extending beyond ROS-responsive systems, Zhang et al. engineered an MMP-9-responsive hydrogel by crosslinking oxidized dextran with an MMP-9-cleavable peptide (PG-6) to encapsulate M2 macrophage-derived exosomes. During initial healing phases, this hydrogel primarily functions to maintain a moist wound environment. As inflammation progressed and MMP-9 levels increased, accelerated degradation triggered exosome release, reprogramming macrophages and enhancing regeneration [103]. This MMP-9-responsive design provides a dynamic “integrated diagnosis and treatment” strategy by synchronizing therapy with the inflammatory state.

4.3 Inhibit Bacterial Colonization

Responsive hydrogels enable targeted antibacterial action through controlled drug release triggered by pathological microenvironment cues. Key approaches include pH-, ROS-, and glucose-responsive antibacterial systems. For pH-responsive antibiotic-dependent platforms, Shao et al. engineered an OCMC-PEI/Tob hydrogel where acidic conditions (pH=5.0) cleave Schiff bases to enable spatiotemporal tobramycin release. This system demonstrated broad-spectrum antibacterial activity through synergistic Tob/PEI action, accelerating healing in P. aeruginosa-infected diabetic wounds [104]. To address antibiotic resistance concerns, hydrogels with intrinsic antimicrobial activity like chitosan derivatives have been engineered [105-111]. Wang et al. developed a dual-crosslinked HTCC/OD-DA hydrogel incorporating silver nanoparticles (Ag NPs), where acid-triggered Schiff base cleavage released Ag NPs at over threefold physiological concentrations, thereby enhancing both antibacterial and angiogenic functions (Figure 4A) [112]. Similarly, Li et al.'s pH-responsive IKFQFHFD peptide hydrogel self-assembles at neutral pH but dissociates in acidity, releasing inherent biofilm-disrupting antimicrobials that promote diabetic wound repair (Figure 4B) [113]. Building on the concept of stimuli-responsive hydrogels, Yang et al. designed a ROS-responsive hydrogel system, TSPBA/PVA/l-Arg. In this system, elevated levels of hydrogen peroxide (H₂O₂) oxidize l-arginine (l-Arg) to generate nitric oxide (NO). Sustained NO release reacts with ROS to produce peroxynitrite, conferring prolonged antibacterial activity while modulating collagen deposition [114]. Complementing these approaches, glucose-responsive cascade systems have been engineered to exert antibacterial effects through the controlled release of metal ions. For instance, Yang et al. developed the IDA-Zn²⁺/GOx/DFO hydrogel (DG@Gel), which exploits glucose-derived acidification (pH≈4.3) to release Zn²⁺ ions, thereby achieving concurrent antibacterial and angiogenic effects [115]. Furthermore, Fenton reaction platforms have been employed. A representative example is Liu et al.'s CS@SBE-β-CD@Fe²⁺-GOx hydrogel, which utilizes glucose-generated H₂O₂ to drive Fe²⁺-mediated •OH production via Fenton reactions. These radicals exerted potent antibacterial effects in hyperglycemic environments while promoting epithelialization [116]. Similar •OH-generation strategies employ CuO/Cu-MOF nanoparticles integrated with GOx-loaded hydrogels [117, 118].

4.4 Exert Antioxidant Effects

Given the spatially localized and temporally fluctuating nature of oxidative stress in diabetic wounds, ROS-responsive hydrogels offer a promising strategy for achieving spatiotemporal drug release through site-specific, redox-triggered mechanisms [119-125]. Among synthetic ROS-responsive units, PBAEs and their derivatives are prominent for their selective cleavage in ROS-enriched microenvironments [126-128]. For instance, Niu et al. developed a novel ROS-responsive hydrogel by sequentially incorporating DL-Dithiothreitol (DTT), poly(ethylene glycol) diacrylate (PEGDA), and phenylboronic acid-modified ε-Poly-l-lysine (EPL-PBA). This hydrogel effectively scavenged H₂O₂, enhanced EPL release, modulated the wound microenvironment, and accelerated healing [129]. Beyond synthetic systems, naturally derived amino acids, particularly cysteine, enable the design of ROS-responsive biomaterials. The strategic linkage of amino acids via amide bonds facilitates the synthesis of functional peptides with diverse sequences [130, 131]. Crucially, cysteine possesses a thiol group (-SH) that undergoes ROS-triggered oxidation to form disulfide bonds [132]. Li et al. demonstrated this principle using genetically encoded hydrogels containing RGD and cysteine-proline-proline-cysteine (CPPC) peptides. H₂O₂ exposure induced disulfide cross-linking between CPPC terminal cysteines, while subsequent ROS elevation cleaved these bonds, triggering a gel-to-sol transition, ROS scavenging, and accelerated epithelial regeneration [133]. Natural polyphenolic antioxidants, such as catechin and epigallocatechin gallate (EGCG), have also been integrated into responsive hydrogels [134-141]. Sun et al. synthesized a glucose-responsive hydrogel (GMPE) by modifying gelatin methacryloyl (GelMA) with 4-carboxyphenylboronic acid (CPBA) and encapsulating EGCG. At diabetic wound sites, elevated glucose triggered cleavage of the boronic ester bonds between CPBA and EGCG's ortho-dihydroxy groups, enabling rapid EGCG release and promoting healing [142]. Similarly, our group developed a glucose-responsive hydrogel (HMPC) by modifying hyaluronic acid methacrylate (HAMA) with PBA to load catechin. High glucose concentrations at the wound site cleaved the PBA-catechin borate ester bonds, facilitating spatiotemporal catechin release. The HMPC hydrogel protected cells from ROS in vitro and significantly accelerated diabetic wound healing over 3 weeks by reducing inflammation and promoting angiogenesis [143]. Furthermore, enzyme-responsive systems, such as MMP-responsive hydrogels, enable precise drug release in protease-rich wound environments [144-147]. Li et al. fabricated a hydrogel by grafting EGCG and GelMA onto oxidized hyaluronic acid for delivering resveratrol nanoparticles. This hydrogel exhibited rapid degradation (residual mass ~18.06% within 48 h) in MMP-rich conditions, primarily due to the MMP-sensitive GelMA component. In vitro and in vivo studies confirmed the precise release of polyphenol nanoparticles, effectively mitigating oxidative stress in diabetic wounds [148].

4.5 Promote Angiogenesis

Chronic inflammation and hyperglycemia in diabetic wounds drive sustained overexpression of MMPs, leading to excessive ECM degradation and proteolysis of essential proangiogenic growth factors, such as vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β) [149-151]. To counteract this pathological microenvironment, MMP-responsive hydrogels have been engineered using cleavable peptide substrates, metal-chelating agents, or natural ECM analogs [152-154]. One representative strategy utilizes MMP-cleavable peptides covalently integrated into hydrogel networks. Chen et al. developed an MMP-degradable polyethylene glycol hydrogel (MMP-PEG) via Michael addition between thiol groups on an MMP-sensitive peptide and maleimide groups on 4-arm-PEG-MAL. This hydrogel encapsulated adipose-derived stem cell exosomes for diabetic wound treatment. It demonstrated high responsiveness, releasing > 90% of exosomes in MMP-2 solution over 20 days versus < 10% in PBS. In vivo, the MMP-triggered release significantly accelerated wound repair by enhancing neovascularization and collagen deposition [155]. Alternatively, MMP-sensitive hydrogels can leverage natural ECM component degradation. Hu et al. fabricated a hydrogel through Schiff base formation between oxidized hyaluronic acid (HA-CHO) and hydrazide-modified gelatin (Gel-ADH), loading the TRPA1 agonist cinnamaldehyde (CA). This hydrogel underwent complete degradation under MMP-rich conditions in vitro within 5 days. The rapid, MMP-responsive degradation enabled sustained CA release, which inhibited high glucose-induced endothelial cell ferroptosis, alleviated vascular dysfunction, and promoted angiogenesis [156].

5.1 pH/ROS-Responsive Hydrogels for Diabetic Wound Healing

Diabetic wounds exhibit a pathological microenvironment characterized by spatiotemporal fluctuations in acidity and elevated ROS levels, which exacerbate bacterial infection, metabolic dysregulation, and chronic inflammation. To address this dynamic milieu, dual pH/ROS-responsive hydrogels have been engineered for spatiotemporally controlled drug release [157, 158]. These systems exploit two synergistic mechanisms: (i) the formation of reversible boronic ester bonds between phenylboronic acid (PBA) and diols at physiological pH (pK_a 7.8–8.6), hydrolyzing under acidic conditions [159]; and (ii) the dissociation of Schiff base linkages (imine bonds) between aldehydes and amines in acidic microenvironments [160]. Both bonds exhibit ROS sensitivity, enabling dual-triggered hydrogel disassembly. Wang et al. engineered an interpenetrating network from caffeic acid-grafted ε-polylysine (CE) and PBA-grafted oxidized dextran (POD). Acidic/ROS-rich wound conditions triggered cleavage of boronic ester and Schiff base bonds, releasing diclofenac sodium and mangiferin to accelerate healing (Figure 5A) [161]. Similarly, Li et al. synthesized HA-CHO-BA hydrogel via Schiff base conjugation of hyaluronic acid (HA-CHO) and 3-aminophenylboronic acid (BA) within a PVA matrix. The pH/ROS-responsive hydrogel, loaded with silver-doped polydolamine nanoparticles and recombinant human collagen III, mitigated inflammation and enhanced angiogenesis through triggered disintegration [163]. Advanced designs encapsulate therapeutics within stimuli-sensitive carriers embedded in hydrogel matrices, enabling phase-specific release [164-166]. Kong et al. incorporated ROS-sensitive paeoniflorin micelles into a pH-responsive gelatin-dextran hydrogel. Acidic-triggered ZnO nanoparticle release controlled initial infection, while subsequent ROS-mediated micelle degradation released paeoniflorin to promote angiogenesis [167]. To augment ROS scavenging, nanozymes mimicking superoxide dismutase (SOD)/catalase (CAT) activities have been incorporated [168-172]. These degrade O₂•⁻ to H₂O₂ and further to H₂O/O₂, alleviating oxidative stress [173-177]. Zhang et al. developed an in situ-gelling system using ε-polylysine (EPL)-coated MnO₂ nanozymes and aldehyde-modified F127 micelles encapsulating insulin. ROS-triggered MnO₂ catalysis and Schiff base cleavage promoted gel degradation, enabling spatiotemporal insulin release while scavenging ROS, supplying O₂, and modulating glucose (Figure 5B) [162]. Clinical translation of ROS/pH dual-responsive hydrogels faces challenges. Balancing pH and ROS responsiveness within a single hydrogel system remains complex due to significant microenvironmental variations across diabetic wounds. Moreover, biodegradability and biocompatibility require rigorous optimization, particularly when incorporating nanoparticles or drug conjugates.

5.2 pH/Glucose-Responsive Hydrogels for Diabetic Wound Healing

Diabetic wounds exhibit an acidic and hyperglycemic microenvironment, rendering pH/glucose dual-responsive hydrogels a strategic platform for spatiotemporally controlled drug delivery. PBA serves as a pivotal moiety in these systems, responding to pH fluctuations and glucose via reversible binding with 1,2-diol structures [178-181]. This enables glucose-mediated spatial targeting and pH-triggered temporal release synchronized with inflammatory dynamics. Synthetic polymer matrices functionalized with PBA demonstrate targeted drug release. Ni et al. synthesized a hydrogel (PP) via PBA-diol crosslinking between poly(acrylamide-co-dimethylaminopropylacrylamide-co-methacrylamidophenylboronic acid) (PB) and PVA. Embedded antibiotic-loaded mesoporous silica nanoparticles (MSN@PDA-TH) exhibited accelerated release under acidic/high-glucose conditions through PBA-glucose competition and PBA-PVA bond dissociation, effectively targeting infected diabetic wounds [182]. In addition, natural polymer systems leverage PBA functionality. Cao et al. developed an injectable HQB hydrogel from hyaluronic acid-PBA (HA-PBA), quaternized chitosan (QCS), and Mg²⁺-containing bioactive glasses (MgBGs). pH/glucose-triggered boronate ester cleavage enabled controlled MgBG release, accelerating wound repair [183]. Furthermore, hybrid matrices incorporating Schiff bases enhance responsiveness [184]. Zhao et al. engineered a hydrogel using phenylboronic acid-modified chitosan (CSPBA), PVA, and benzaldehyde-capped PEG (OHC-PEG-CHO), encapsulating insulin and fibroblasts. Synergistic disruption of Schiff base bonds and PBA-glucose interactions under acidic pH (6.5) and high glucose (3 g/L) significantly enhanced insulin release versus physiological conditions, promoting neovascularization and collagen deposition (Figure 6A) [185]. Extending this strategy to type II diabetes (90%–95% of cases), Guo et al. loaded metformin and polydopamine-coated graphene oxide (rGO@PDA) into a Schiff base-linked hydrogel (PC). Acidic-triggered hydrolytic cleavage (30.4% increased release at pH 5.5) combined with glucose-induced matrix collapse enabled spatiotemporal delivery, suppressing oxidative stress and accelerating angiogenesis in vivo (Figure 6B) [186]. Despite their promise, key limitations persist. Dynamic pH/glucose fluctuations may cause inconsistent drug release, while PBA integration compromises mechanical integrity in hyperglycemic environments [187-189].

5.3 Other Dual-Responsive Hydrogels for Diabetic Wound Healing

Although pH-responsive hydrogels dominate current dual-responsive systems for diabetic wounds, the complexity of wound pathophysiology necessitates strategies integrating broader biological triggers [190-197]. Platforms responsive to cues beyond pH remain under-explored [198, 199]. Addressing this, Fan et al. developed a glucose/MMP-9 dual-responsive hydrogel composed of cross-linked polyvinyl alcohol (PVA) and phenylboronic acid-modified chitosan (CS-BA). This hydrogel was engineered to co-load insulin and gelatin microspheres encapsulating celecoxib (GMs@Cel). In this system, the PBA groups conferred glucose sensitivity, enabling reversible swelling and controlled insulin release via competitive glucose binding. Simultaneously, gelatin microspheres undergo enzyme-triggered degradation upon encountering elevated MMP-9 levels, significantly accelerating celecoxib release. Concurrent glucose and MMP-9 stimulation, hydrogel disintegration was accelerated, enabling synchronized release of insulin and celecoxib. Notably, release kinetic analysis revealed that insulin release was predominantly diffusion-driven, while celecoxib release followed a non-Fickian model influenced by both microsphere degradation and molecular diffusion. This design strategically aligns dual-stimuli responsiveness with spatiotemporally distinct cues in the diabetic wound environment. Glucose acts as a systemic metabolic marker. MMP-9 serves as a localized indicator of inflammatory tissue remodeling. By coupling these cues, the hydrogel achieves on-demand, sequential drug release of anti-inflammatory and metabolic-regulating agents, effectively coordinating the early and late phases of diabetic wound healing. This dual-responsive platform demonstrated accelerated wound closure, enhanced collagen deposition, and improved modulation of the local immune microenvironment in vivo [200]. Therefore, integrating multiple pathological cues beyond pH represents a promising strategy for adaptable and precise diabetic wound therapies.