A Core–Shell Nanotherapeutic Platform Reprograms the Infected Wound Microenvironment through Dual Bactericidal and Immunomodulatory Actions for Accelerated Healing
Aug 2026· ACS Applied Materials & Interfaces· 0 citations· 53 references
TL;DR
A core–shell-type ZnO@ZIF-8/Ag nanocomposite material that combines high antibacterial activity with excellent biocompatibility offers a strategy for developing therapies against drug-resistant bacterial infections with the potential for clinical application.
Abstract
The treatment of wounds caused by drug-resistant bacteria is a significant challenge in clinical medicine. Silver (Ag) nanoparticles have attracted considerable attention due to their ability to inhibit drug-resistant bacteria. Nevertheless, the propensity of Ag nanoparticles to aggregate as well as their elevated toxicity have restricted their practical application. To address this issue, this study involved the design of a core–shell-type ZnO@ZIF-8/Ag nanocomposite material that combines high antibacterial activity with excellent biocompatibility. The mean diameter of the Ag nanoparticles in this material was approximately 2.4 nm, and they were highly dispersed. Within the wound microenvironment, antibacterial factors, such as hydroxyl radicals (·OH), singlet oxygen (1O2), Zn2+, and Ag+, were generated. The material induced bacterial death by altering the structure of the cell wall of drug-resistant bacteria, thereby inhibiting respiration, lysing phospholipid layers, and causing cellular content leakage. The introduction of zinc oxide (ZnO) significantly reduced the toxicity of the Ag nanoparticles and regulated macrophage polarization, which inhibited the secretion of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) by M1-type macrophages (M1) while concomitantly promoting the secretion of interleukin-10 (IL-10) and vascular endothelial growth factor by M2-type macrophages (M2). The expression of platelet-endothelial cell adhesion molecule-1 (CD31), type I collagen/fibronectin (COL-I/FN), and proliferating cell nuclear antigen (PCNA) was significantly promoted, which significantly enhanced wound healing in infected wounds. This study thus offers a strategy for developing therapies against drug-resistant bacterial infections with the potential for clinical application.
The refractory healing of diabetic wounds represents a major clinical challenge, primarily attributed to a vicious cycle formed by persistent bacterial infection, excessive oxidative stress, and a dysregulated immune microenvironment. To simultaneously address multiple pathological barriers, an intelligent composite nanoplatform was designed and constructed in this study, integrating near-infrared (NIR) photothermal therapy, reactive oxygen species (ROS) scavenging, antimicrobial activity, and immunomodulation. A mesoporous polydopamine (MPDA) core was loaded with chlorogenic acid (CGA), a natural antioxidant, and further coated with a copper-zinc bimetallic organic framework (Cu/Zn-MOF) to fabricate Cu/Zn-MOF@CGA@MPDA NPs, exhibiting pH-responsive dissociation in the acidic infected wound microenvironment. Under 808 nm near-infrared irradiation, the fabricated NPs showed excellent photothermal performance, efficiently eliminating bacteria and biofilms in vitro. They also scavenged ROS to relieve oxidative damage and promoted macrophage polarization from the pro-inflammatory M1 to pro-healing M2 phenotype. In a diabetic rat model of infected full-thickness skin wounds, the nanoplatform achieved antibacterial and anti-inflammatory effects simultaneously. Such synergistic functions promoted collagen deposition and re-epithelialization, thereby accelerating diabetic wound healing. Histological and hematological tests verified its good biocompatibility and biosafety. This work developed a synergistic single-platform strategy for precise regulation of diabetic wound microenvironments, providing a promising therapeutic alternative for refractory diabetic wound treatment.
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
Bacterial infection impeded wound healing, causing significant discomfort and endangering the lives of patients. Overusing antibiotics to address such infections has spurred drug resistance in certain pathogenic bacteria. Hence, there is a pressing demand for a non-antibiotic-dependent versatile dressing to amplify on-site antibacterial efficacy, effectively averting wound infections, and fostering wound recovery. In this study, a pioneering near-infrared activated antibacterial EPLGA/OHADA@HMCuS hydrogel was formulated by doping hollow mesoporous copper sulfide (HMCuS) into the three-dimensional spatial network structure formed between gallic acid-modified ε-polylysine (EPL-GA) and dopamine-engineered and oxidized hyaluronic acid (OHADA). This hydrogel not only exhibited exceptional mechanical characteristics and tissue adhesion but also showcased favorable biocompatibility, sustaining cellular viability. The obtained EPLGA/OHADA@ HMCuS hydrogel not only demonstrated robust antibacterial activity against E. coli and S. aureus under laser irradiation but also exhibited a pronounced cell migration-promoting effect. In mouse models of tail amputation and liver injury, this hydrogel exhibited remarkable hemostatic capabilities and was also capable of substantially expediting wound healing in bacterial-infected wounds-bearing rats, as evidenced by its promotion of collagen deposition and angiogenesis, along with the downregulation of inflammatory factors. Hence, this multifunctional EPLGA/OHADA@HMCuS hydrogel stands out as a highly promising wound-assisting material, exhibiting broad potential for clinical application in the future management of infected wounds.
N. Wang, Wei Jiang, Feiyu Lu et al.· Biomaterials Advances· 0 citations
Bacterial biofilms severely compromise antibiotic efficacy and accelerate drug resistance. Herein, a dual-functional nanoplatform (Ga-PDA NPs) was constructed through the coordination-driven assembly of gallium ions (Ga3+) and polydopamine (PDA) for synergistic photothermal and metabolic antibiofilm therapy. The PDA matrix serves as both a high-efficiency photothermal agent and a pH-responsive ligand, facilitating Ga3+ release within the acidic biofilm microenvironment. Under near-infrared irradiation, Ga-PDA NPs generate heat to disrupt bacterial membranes and the extracellular matrix. Concurrently, the released Ga3+ functions as a "Trojan horse," penetrating bacterial cells to interfere with iron metabolism, thereby triggering lethal iron starvation and widespread metabolic dysfunction. In vitro experiments verified potent bactericidal activity against Pseudomonas aeruginosa and Staphylococcus aureus. Moreover, when incorporated into bacterial cellulose membranes, this composite system exhibited excellent biocompatibility and effectively promoted the healing of biofilm-infected wounds in mice. Overall, this dual-functional nanoplatform provides a promising therapeutic strategy for the management of biofilm-associated infections.
Xinyan Zheng, Jie Chen, Tongtong Yin et al.· Biomacromolecules· 0 citations
Impaired infected wound healing is closely associated with mitochondrial dysfunction, and ferroptosis has emerged as a key mechanism connecting oxidative stress to mitochondrial damage. Baicalein holds potential for modulating this process, yet its application is constrained by poor bioavailability. Herein, a multifunctional nano-delivery system (Ba@Zn-MSN@CH) was rationally designed for infected wound treatment. Zinc-doped mesoporous silica nanoparticles (Zn-MSN) were synthesized to serve as a baicalein carrier. Carboxymethyl chitosan (CMCS) and dihydrocaffeic acid were covalently grafted onto the surface of the nanoparticles via silanization and amidation reactions, leading to the formation of a stable core-shell structure. The introduction of macromolecular coating was found to not only prolong drug release but also enhance antioxidant and antibacterial efficacy. What's more, Ba@Zn-MSN@CH effectively alleviated mitochondrial damage by inhibiting ferroptosis, thereby restoring cell proliferation, migration, and angiogenesis, and ultimately accelerating infected wound healing. Mechanistically, Ba@Zn-MSN@CH inhibited ferroptosis by inducing AMP-activated Protein Kinase α (AMPKα) phosphorylation in fibroblasts. AMPKα sustained the abundance of nuclear factor erythroid 2-related factor 2 (Nrf2), which subsequently suppressed lipid peroxidation and inhibited ferroptotic cell death through upregulation of downstream antioxidant factors. Collectively, these findings demonstrated that Ba@Zn-MSN@CH accelerated infected wound healing by inhibiting ferroptosis through activation of the AMPK/Nrf2 signaling pathway, highlighting the potential of baicalein-based nanotherapeutics as a promising strategy for infected wound management.
Mengya Cai, Weijian Chen, Chao Lu et al.· Biochemical and Biophysical...· 0 citations
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.
Chuanliang Fu, Wenjing Zhang, Renyuan Wang et al.· Materials Today Bio· 0 citations