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 (ADSC)-derived exosomes (Exos) were firstly loaded into Ag@bovine serum albumin (BSA) nanoflowers (Exos-Ag@BSA NFs) to form a protective "pollen-flower" delivery structure, which were 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 could selectively dissociate in an oxidative wound microenvironment, which triggered sustained release of Ag ions (Ag + ) and cascaded 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 eliminated bacteria and promoted the apoptosis of impaired oxidative cells, resulting in improved regenerative microenvironment. Additionally, Exos-Ag@BSA NFs/Col markedly accelerated wound healing and regeneration in vivo in a diabetic murine silicone-splinted excisional wound model by promoting blood perfusion, tissues granulation, collagen deposition, neovascularization, angiogenesis, and re-epithelization. We anticipate that this work will inspire the development of more delicate and disease-specific therapeutic systems for clinical wound management. This article is protected by copyright. All rights reserved.