Oxidative Stimuli-Responsive "Pollen-Like" Exosomes from Silver Nanoflowers Remodeling Diabetic Wound Microenvironment for Accelerating Wound Healing

The hostile oxidative wound microenvironment, defective angiogenesis, and uncontrolled release of therapeutic factors are major challenges in improving the diabetic wound healing. Herein, adipose-derived-stem-cell-derived exosomes (Exos) are first loaded into Ag@bovine serum albumin (BSA) nanoflowers (Exos-Ag@BSA NFs) to form a protective "pollen-flower" delivery structure, which are further encapsulated into the injectable collagen (Col) hydrogel (Exos-Ag@BSA NFs/Col) for concurrent remodeling of the oxidative wound microenvironment and precise release of Exos. The Exos-Ag@BSA NFs can selectively dissociate in an oxidative wound microenvironment, which triggers sustained release of Ag ions (Ag+) and cascades controllable release of "pollen-like" Exos at the target site, thus protecting Exos from oxidative denaturation. Such a wound-microenvironment-activated release property of Ag+ and Exos effectively eliminates bacteria and promotes the apoptosis of impaired oxidative cells, resulting in improved regenerative microenvironment. Additionally, Exos-Ag@BSA NFs/Col markedly accelerates wound healing and regeneration in vivo in a diabetic murine silicone-splinted excisional wound model by promoting blood perfusion, tissue granulation, collagen deposition, neovascularization, angiogenesis, and re-epithelization. It is anticipated that this work will inspire the development of more delicate and disease-specific therapeutic systems for clinical wound management.