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.
Keywords: angiogenesis; diabetic wound healing; exosomes; redox homeostasis; silver nanoflowers.
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