Infectious wounds pose a persistent clinical challenge, further aggravated by the rising prevalence of antibiotic-resistant pathogens, which significantly impair therapeutic efficacy and patient prognosis. Addressing the pressing need for effective interventions against multidrug-resistant (MDR) bacterial infections necessitates the development of next-generation therapeutic platforms capable of simultaneously achieving infection control, immune modulation, tissue regeneration, and real-time therapeutic monitoring. Herein, we report the rational design of an A-π-D-π-A conjugated hybrid photosensitizer (TPAB-Cu2+) with potent photodynamic antibacterial activity and fluorescence responsiveness to the infectious microenvironment. By incorporating natural herbal emodin and modified hyaluronic acid, a spatiotemporally responsive hybrid hydrogel (EM@mHA-TPAB-Cu2+) is fabricated via dynamic Schiff base crosslinking. Upon light activation, the hydrogel generates abundant reactive oxygen species (ROS), enabling efficient eradication of MDR bacteria and disruption of mature biofilms. Moreover, the sustained release of emodin scavenges excessive ROS and reprograms the immune microenvironment, thereby facilitating the transition from inflammation to cellular proliferation and tissue remodeling. In vivo studies confirm that this intelligent hydrogel effectively eliminates MDR bacteria, mitigates inflammation, accelerates tissue regeneration, and enables real-time fluorescence monitoring of the therapeutic process. This spatiotemporally responsive hydrogel dressing system, integrating therapeutic and monitoring capabilities, offers significant promise for advanced management of infected wounds.

Critical limb ischemia (CLI) is limited by the inability of conventional therapies to timely alleviate ischemia-induced inflammatory response and tissue damage. While cell-based therapies have significant potential, their efficacy is constrained by poor cell retention and survival. Inspired by natural extracellular matrix, we developed hierarchical porous microspheres with bionic niche to enhance cell therapy. Small intestinal submucosal decellularized extracellular matrix (SIS-dECM) was selected as the main component, and gelatin methacrylate (GelMA) was introduced to provide suitable mechanical properties and controllable photocrosslinking. An innovative strategy was employed by further introducing polyethylene glycol (PEO) to utilize liquid-liquid phase separation within a dECM-dominated ternary hybrid system, which enabled precise control of the pore and produced interconnected primary macropores (43.3 ± 15.4 μm). Secondary pores were constructed via ice-templating method. Finally, microspheres were modified with fibronectin (FN) to enhance bioactivity. This biomimetic design in biochemical composition, physical structure, and interfacial functionalization enables deep cell infiltration, high cell-loading, and cytoprotection, while maintaining human umbilical cord mesenchymal stem cells (HUMSCs) stemness and enhancing their tri-lineage differentiation potential and paracrine activity. To further promote vascularization, we co-load human umbilical vein endothelial cells (HUVECs) with HUMSCs to form a synergistic system (G-FN@EC/MSC), which demonstrated superior angiogenesis and macrophage M2 polarization in vitro. This treatment achieved high blood flow recovery (94.23% ± 1.42% at day 21) in vivo, with substantial improvement in muscle regeneration and inflammation modulation. This work establishes a new paradigm for fabricating biomimetic microspheres and synergistic cell therapy for CLI.

Lung ischemia-reperfusion injury and severe pneumonia represent major clinical challenges with high mortality rates and a lack of effective targeted therapies after lung transplant. Their pathogenesis involves multiple factors, including immune dysregulation, oxidative stress, and mitochondrial dysfunction, which limit the efficacy of single-target treatment strategies. This study developed a novel biohybrid nanovesicle system (Res-PD-L1@nmEVs) that integrates the inflammatory targeting capability of neutrophil membrane-derived vesicles, the tissue repair and immunomodulatory functions of PD-L1-overexpressing mesenchymal stem cell extracellular vesicles, and the mitochondrial protective effects of resveratrol. Following nebulized administration, the system demonstrated enhanced pulmonary accumulation and efficient uptake by injured epithelial cells. In vitro experiments confirmed that Res-PD-L1@nmEVs inhibited inflammation and oxidative stress, reduced apoptosis, and restored mitochondrial integrity by activating PINK1-mediated mitophagy and promoting mitochondrial repair, thereby mitigating hypoxia-reoxygenation-induced injury in lung epithelial cells. The delivery of PD-L1 via Res-PD-L1@nmEVs binding to PD-1 on neutrophil membranes suppressed neutrophil activation and alleviated the release of inflammatory factors. In rat models of lung ischemia-reperfusion injury and methicillin-resistant Staphylococcus aureus-induced pneumonia, nebulized administration of Res-PD-L1@nmEVs significantly attenuated lung tissue damage, inhibited neutrophil activation, reduced inflammatory cytokine release, improved alveolar barrier integrity, promoted the recovery of pulmonary function, and alleviated hypoxemia. Transcriptomic analysis revealed that the treatment synergistically enhanced energy metabolism and biosynthetic processes while suppressing inflammatory pathways. This study presents a comprehensive targeted strategy that simultaneously addresses immune dysregulation, oxidative damage, and metabolic dysfunction in inflammatory lung diseases, demonstrating significant potential for clinical translation.

The tissues spanning from tendon to bone exhibit a highly specialized extracellular matrix (ECM) architecture, characterized by hierarchical collagen alignment and a gradient mineral composition, which together enable efficient force transfer and guide spatially organized cellular phenotypes. However, recapitulating such complex multi-scale organization and compositional gradients to achieve integrated soft-hard tissue remains challenging. Here, we report the de novo construction of biomimetic collagen–mineral matrices that mimic both the hierarchical organization and mineral gradient distribution of the native tendon-to-bone ECM. Through synergistic electro-assembly and post-treatment, collagen molecules self-organized into aligned fibrillar matrices with multi-scale architecture, replicating tendon-side morphology while providing robust tensile mechanics. At the opposing end, intrafibrillar and interfibrillar minerals were spatially patterned to emulate the mineral gradient from tendon to bone. This structural and compositional continuum enables smooth mechanical transition across the soft-hard tissue interface and promotes region-specific regeneration of aligned tendon-like tissue, fibrocartilage and bone. In vivo studies in rabbit models confirm that these de novo constructed matrices support histological reconstruction of multiple tissues from tendon to bone at the rotator cuff, and significantly improve functional recovery. This work presents a bottom-up biomimetic strategy for engineering multiscale collagen-based scaffolds and demonstrates the therapeutic potential of de novo constructed matrices for multiple tissue regeneration.