Supermolecular poly-N-acryloyl glycinamide/polyglutamic acid/Fe3+ hydrogel incorporated with bioactive small extracellular vesicles promote diabetic wound healing by suppressing ferroptosis

Poorly-controlled blood glucose frequently develop in diabetic wounds and hydrogel has been reported of great performance for diabetic wound healing. Consequently, we prepared poly-N-acryloyl glycinamide (PNAGA) and introduced polyglutamic acid (γ-PGA), Fe 3+ , small extracellular vesicles (sEVs) into PNAGA to form a dual physical cross-linking supramolecular hydrogel system (PFF) for diabetic wound healing. In this study, we successfully synthesized the PFF hydrogel and extracted the sEVs that were incorporated into PPF as PPF/sEVs. In our research, we find that PFF hydrogel possessed continuous porous structure and, exceptional resilience, excellent extensibility and flexibility, closely mimicking the mechanical performance of human skin. Moreover, the PFF/sEVs hydrogel could release sEVs, playing a critical role in wound healing. Our results showed PFF/sEVs hydrogel improved the wound healing characterized by shorter wound closure time and enhanced blood vessel density in vivo. Also, sEVs counteracted the inhibitory effects of high glucose on proliferation, migration, tube differentiation, malondialdehyde (MDA) and glutathione (GSH) levels, which may attribute to the inhibition of ferroptosis by influencing free fatty acids (FFA) metabolism in vitro. Our findings indicated that the low-cost, biocompatible, and multifunctional bioactive PFF supramolecular hydrogel loaded with sEVs hold tremendous application potential as a clinical platform for diabetic wound healing.