Oxidative Stimuli‐Responsive “Pollen‐Like” Exosomes from Silver Nanoflowers Remodeling Diabetic Wound Microenvironment for Accelerating Wound Healing

Abstract

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.

Recent advances of hydrogels as smart dressings for diabetic wounds

“…This ROS consumption strategy effectively protects Exos from oxidative denaturation, promotes the safe delivery of Exos, and accelerates wound regeneration. 165 Iron death is a newly discovered form of regulated cell death characterized by iron overload and iron-dependent lipid peroxidation in the cell. High glucose environments can inhibit wound angiogenesis by inducing iron death and damaging the proliferation, migration, and tube formation abilities of human umbilical vein endothelial cells (HUVECs).…”

Hydrogel-based dressings designed to facilitate wound healing

“…They promote rapid wound healing through mechanisms involving angiogenesis promotion and inflammation modulation. 135–138 Yang et al conducted a study where they encapsulated exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-exos) within a thermosensitive hydrogel called Pluronic F-127 (PF-127). They used a full-thickness wound model in diabetic rats and found that the combination of PF-127 hydrogel with hUCMSC-exos led to increased production of CD31 and upregulation of VEGF expression.…”

Biomaterial‐Facilitated Local Delivery of Stem Cell‐Derived Small Extracellular Vesicles: Perspectives in Surgical Therapy

“…Chen et al first loaded adipose MSC-derived sEVs into silver nanoflowers to form a protective "pollen-like" delivery system, which was further incorporated into an injectable collagen HG for concurrent remodeling of the oxidative wound microenvironment and precise release of sEVs. [125] Bakadia et al developed a dual-crosslinked HG based on silk proteins (fibroin and sericin) for local delivery of BM MSC-derived sEVs and platelet-rich plasma-derived sEVs. [126] In addition, Zhang et al fabricated a bioinspired adaptable indwelling polyvinyl alcohol (PVA) HG microneedle, [127] whereas Li et al produced an SF patch for local delivery of miR-146a-engineered placental MSC-derived sEVs.…”