Organic–Inorganic Nanocomposite Hydrogels Remarkably Enhance Skin Regeneration in Burn Wound Healing by Targeting Neurovascular Network Reconstruction

Severe burn injuries pose a critical challenge due to the destruction of neurovascular networks, which are indispensable for skin regeneration and often lead to incomplete healing and functional deficits. This study introduces an organic-inorganic nanocomposite hydrogel that orchestrates neurovascular network reconstruction to achieve full-thickness skin regeneration in burn wounds. Composed of gelatin-based matrices embedding mineralized metal-phenolic nanoparticles (MMF) and stem cell-derived exosomes (EXO), this "dual-engine" system synergizes MMF's ion-releasing (Zn²⁺, SiO₃^2-, tannic acid) and EXO's bioactive signaling to overcome regeneration barriers. MMF stabilizes vascular architectures while exerting antioxidant and antibacterial effects, whereas EXO enhances endothelial cell migration and tube formation. In a murine deep second-degree burn model, the nanocomposite hydrogel could accelerate the wound closure rate (reaching 96.9% within 15 days, four times faster than controls), enhance collagen deposition, promote angiogenesis and innervation (increase vascular density by over 2-fold and nerve fiber regeneration by 3.5-fold), facilitate scarless wound healing (with epidermis thickness comparable to that of native skin), and stimulate skin appendage regeneration (the density of hair follicles/glands was approximately 7.8 times that of controls). In summary, our work offers an attractive approach to designing biomaterials that promote neurovascular regeneration and wound healing in burn injuries.