An infection-responsive multifunctional hydrogel enables potent activity against methicillin-resistant Staphylococcus aureus and promotes wound healing
Gel-P@Z exhibited a slow and sustained release of Gly-POX and achieved >99% antibacterial efficacy against drug-resistant bacteria without toxicity, and RNA-seq analysis revealed that Gel-P@Z accelerated healing via upregulation of the TGF-β signaling pathway, driving fibroblast-to-myofibroblast transition and promoting tissue fibrosis.
Abstract
Infected wounds remain a significant clinical challenge due to bacterial resistance and impaired healing. Therefore, developing effective antibacterial agents and precise delivery systems is crucial for rapid wound repair. To address this, we constructed zeolitic imidazolate framework-8 (ZIF-8) nanoparticles loaded with the host defense peptide-mimicking glycine-poly(2-oxazoline) (Gly-POX) and incorporated them into methacrylated gelatin (GelMA) to prepare the Gel-P@Z nanocomposite hydrogel. The hydrogel integrates the following core design elements: the pH-responsive degradation of ZIF-8 enables targeted drug release within the infected microenvironment; Gly-POX, mimicking the structure of host defense peptides, exerts membrane-disruptive antibacterial activity against MRSA, which possesses a negatively charged cell membrane, through its positively charged side chains; and the GelMA hydrogel provides a three-dimensional extracellular matrix-like scaffold that supports cell adhesion and proliferation. Gel-P@Z exhibited a slow and sustained release of Gly-POX and achieved >99% antibacterial efficacy against drug-resistant bacteria without toxicity. Moreover, Gel-P@Z promoted macrophage polarization from M1 to M2 phenotype and enhanced efferocytosis, while also facilitating fibroblast migration and inducing contraction in ex vivo fascia explants. In a murine full-thickness MRSA-infected wound model, Gel-P@Z effectively cleared bacteria, modulated the inflammatory microenvironment, and promoted both angiogenesis and collagen deposition. RNA-seq analysis revealed that Gel-P@Z accelerated healing via upregulation of the TGF-β signaling pathway, driving fibroblast-to-myofibroblast transition and promoting tissue fibrosis. This work not only proposes a novel strategy for antibacterial polymer delivery but also offers a promising solution for the management of infected wounds.
Skin wounds are highly susceptible to bacterial invasion, and persistent infection remains a major obstacle to effective tissue repair. Conventional wound dressings often show insufficient antibacterial activity and limited capacity to actively regulate the infected wound microenvironment. Herein, an acid-responsive nanozyme-loaded composite fibrous membrane was developed as a non-antibiotic wound dressing for enhanced chemodynamic antibacterial therapy. Silver nanocubes were encapsulated within zeolitic imidazolate framework-67 to form Ag@ZIF-67 nanozymes, which were subsequently incorporated into electrospun polycaprolactone fibers to obtain Ag@ZIF-67/PCL composite membranes. Under weakly acidic conditions mimicking infected wounds, the ZIF-67 shell underwent microenvironment-triggered decomposition, enabling sustained release of Co2⁺ and Ag⁺. The released Co2⁺ catalyzed the conversion of H₂O₂ into highly toxic hydroxyl radicals through a Fenton-like reaction, while Ag⁺ provided additional broad-spectrum antibacterial activity. Benefiting from this complementary antibacterial mechanism and the extracellular matrix-like fibrous architecture, the Ag@ZIF-67/PCL membrane achieved antibacterial efficiencies exceeding 98% against both Escherichia coli and Staphylococcus aureus after 48 h. Moreover, the composite membrane exhibited favorable cytocompatibility and hemocompatibility, promoted endothelial cell migration, and significantly accelerated the healing of S. aureus-infected wounds in vivo by enhancing re-epithelialization, collagen deposition, and neovascularization. Overall, this study provides a pH-responsive, nanozyme-integrated fibrous membrane with combined antibacterial and pro-regenerative functions, offering a promising strategy for the treatment of bacteria-infected wounds without relying on antibiotics.
Han Lin, Jingyan Huang, Xiaoqi Xie et al.· Colloids and Surfaces B: Bio...· 0 citations
This work demonstrates a safe and effective strategy for combating MDR infections through the combined action of photothermal therapy and nanozyme catalysis, offering promising potential for clinical wound management.
Weiwei Zhang, Lixiang Fan, Xuanjun Zhang et al.· ACS Applied Materials and In...· 0 citations
Hydrogel dressings have emerged as versatile platforms for wound management. However, effective treatment remains challenging due to complex wound environments involving hemorrhage, bacterial infection, and inflammation. Herei, a multifunctional pH-responsive hydrogel (PCOB 1) was developed via multinetwork cross-linking and freeze-thaw cycles using oxidized pullulan (OP), collagen, poly(vinyl alcohol) (PVA), and borax, and was impregnated with in situ stabilized silver nanoparticles (AgNPs). The incorporation of AgNPs endowed the hydrogel with pH-triggered antibacterial activity, achieving >99% killing of E. coli and S. aureus, efficient biofilm disruption, >90% ROS/RNS scavenging, and catalase-mimetic activity. The hydrogel demonstrated rapid gelation, self-healing, and hemostasis within 33.3 s. The hydrogel promoted macrophage polarization from M1 to M2, enhanced collagen deposition, re-epithelialization, and granulation tissue formation, achieving 98.5 ± 0.6% wound closure by day 14 in vivo. This study presents a multifunctional hydrogel with antibacterial, antioxidant, and anti-inflammatory properties for accelerated wound healing.
Muhammad Shahid, Mujahid Niaz, Huma Ghazal et al.· Biomacromolecules· 0 citations
Chronic infected wounds are often characterized by persistent bacterial colonization, biofilm formation, excessive oxidative stress, and prolonged inflammation, which severely impair tissue regeneration. To address these challenges, a multifunctional wound dressing capable of antibacterial activity and microenvironment modulation was developed. In this study, amide-modified hyaluronic acid (HA-ADH) was used as the matrix, and a dynamic coordination network was constructed via Cu2+-hydrazide interactions to form an in situ HA-Cu hydrogel. Curcumin-loaded DSPE-PEG2000 micelles were further incorporated to obtain a pH-responsive composite hydrogel (HA-Cu/Cur). The prepared hydrogel exhibited a porous interconnected structure, along with favorable injectability, self-healing capability, tissue adhesiveness, moderate swelling, controllable degradability, and pH-responsive behavior under acidic conditions. In vitro antibacterial assays demonstrated that both HA-Cu and HA-Cu/Cur effectively inhibited the growth and biofilm formation of Escherichia coli and Staphylococcus aureus. The antibacterial activity was associated with disruption of bacterial morphology, depletion of intracellular ATP, and induction of reactive oxygen species, while HA-Cu/Cur showed enhanced performance in antibiofilm activity and oxidative stress-related effects compared with HA-Cu. Cytocompatibility studies revealed that the hydrogel extracts exhibited negligible cytotoxicity toward L929 fibroblasts and RAW 264.7 macrophages, while promoting fibroblast migration and significantly reducing the expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) in lipopolysaccharide-stimulated RAW 264.7 cells, with HA-Cu/Cur showing a more pronounced anti-inflammatory effect. In summary, the HA-Cu/Cur hydrogel integrates the antibacterial and pro-healing properties of Cu2+ with the antioxidant and anti-inflammatory activities of curcumin. The hydrogel effectively inhibited the growth and biofilm formation of both E. coli and S. aureus, reduced the expression of TNF-α, IL-6, and IL-1β in LPS-stimulated macrophages, and promoted fibroblast migration, demonstrating its potential as a multifunctional wound dressing for the management of infected wounds.
Jiajie Chen, Haotian Huang, Yihan Wang et al.· Molecules· 1 citation
Diabetic chronic wounds remain a major clinical challenge due to persistent infection, excessive inflammation, and impaired tissue regeneration. Herein, we report a multifunctional peptide-based antibacterial hydrogel (PAHG) for treating infected wounds, constructed through the incorporation of Cys-Arg-NH2 (CR)-Ag nanoassemblies into a bioactive matrix. In this design, the CR dipeptide enables in situ reduction and stable coordination of silver ions, yielding CR-Ag nanoassemblies with controlled silver release and enhanced biocompatibility. Co-assembly of this antibacterial component with chitosan, gelatin, collagen, and epidermal growth factor (EGF) affords a three-dimensional hydrogel network that provides a moist wound microenvironment, structural support, and sustained release of pro-regenerative cues. The resulting PAHG system exhibits excellent antibacterial activity against Escherichia coli and methicillin-resistant Staphylococcus aureus, with inhibition efficiencies exceeding 80%, while maintaining high cytocompatibility with human skin fibroblasts (∼150% viability). In a diabetic infected wound model, PAHG significantly accelerates wound healing, achieving nearly complete closure within 12 days, accompanied by enhanced collagen deposition and no noticeable histopathological abnormalities in major organs. By integrating molecularly engineered antibacterial nanoassemblies with rationally designed multicomponent hydrogels, this work provides a promising strategy for the development of bio-based antimicrobial materials and chronic wound dressings.
Heng Ge, Wen Yuan, Yulin Sun et al.· Journal of materials chemist...· 0 citations
Methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds present a significant clinical challenge due to persistent inflammation and impaired tissue regeneration. Here, we developed an IR780SS-engineered hydrogel with a hydrogen-bond-regulated network for infected wound treatment. In this system, IR780SS serves not only as a NIR photosensitizer, but also as an active component that interacts with the hydrogel matrix through hydrogen bonding, hydrophobic interactions, and π-π stacking. These interactions improve the stability and dispersion of IR780SS within the hydrogel and help preserve its photoactivity. Under 808 nm NIR irradiation, the hydrogel generates mild local hyperthermia and abundant ROS, producing antibacterial effects through combined action of PTT and PDT mechanisms. This treatment disrupts bacterial membranes and induces severe oxidative damage inside bacterial cells, leading to the near-complete elimination of drug-resistant bacteria. In a MRSA-infected wound model, rapid bacterial clearance promoted the transition from the inflammatory phase to the proliferative phase and resulted in a wound closure rate of 85.6% on day 11. Histological and immunofluorescence analyses further confirmed improved tissue repair, including enhanced re-epithelialization, angiogenic responses, and collagen remodeling, as evidenced by increased cytokeratin 14 (CK14) and smooth muscle actin (α-SMA) expression, together with more organized collagen deposition. These results suggest that integrating IR780SS into a hydrogen-bonded hydrogel not only enables effective antibacterial phototherapy but also facilitates functional wound reconstruction, providing valuable insight into the clinical development of regenerative dressings for MRSA-infected wounds.