Autophagosomes Defeat Ferroptosis by Decreasing Generation and Increasing Discharge of Free Fe2+ in Skin Repair Cells to Accelerate Diabetic Wound Healing

Abstract Ferroptosis plays an essential role in the development of diabetes and its complications, suggesting potential therapeutic strategies targeting ferroptosis. Secretory autophagosomes (SAPs) carrying cytoplasmic cargoes have been recognized as novel nano‐warrior to defeat diseases. Here, it is hypothesized that SAPs derived from human umbilical vein endothelial cells (HUVECs) can restore the function of skin repair cells by inhibiting ferroptosis to promote diabetic wound healing. High glucose (HG)‐caused ferroptosis in human dermal fibroblasts (HDFs) is observed in vitro, which results in impaired cellular function. SAPs successfully inhibit ferroptosis in HG‐HDFs, thereby improving their proliferation and migration. Further research show that the inhibitory effect of SAPs on ferroptosis resulted from a decrease in endoplasmic reticulum (ER) stress‐regulated generation of free ferrous ions (Fe 2+ ) in HG‐HDFs and an increase in exosome release to discharge free Fe 2+ from HG‐HDFs. Additionally, SAPs promote the proliferation, migration, and tube formation of HG‐HUVECs. Then the SAPs are loaded into gelatin‐methacryloyl (GelMA) hydrogels to fabricate functional wound dressings. The results demonstrate the therapeutic effect of Gel‐SAPs on diabetic wounds by restoring the normal behavior of skin repair cells. These findings suggest a promising SAP‐based strategy for the treatment of ferroptosis‐associated diseases.