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+, SiO32–, 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.