Engineered ADSCs and doxycycline encapsulated antibacterial, immunomodulatory and proangiogenic hydrogels for infected burn wound healing

Burn wounds pose significant clinical challenges due to their complex pathophysiology and infection risks. Adipose-derived stem cell (ADSC)-based therapies have shown promise in treating burn wounds, primarily due to ADSC-derived growth factors. However, ADSCs secrete limited growth factors. Recently, fibroblast growth factor 21 (FGF21) has shown outstanding effects on wound healing, but its impact on infected wounds remains elusive. Herein, the engineered ADSCs overexpressing FGF21 (ADSC^FGF21) and doxycycline (DOX) were encapsulated in a hydrogel network formed by crosslinking between methacrylated hyaluronic acid (HAMA) and methacrylated gelatin (GelMA), resulting in an HG hydrogel. The HG/DOX/ADSC^FGF21 hydrogel dressing exhibited good biocompatibility and injectability. Besides, it showed potent bactericidal effects against MRSA. In vitro studies revealed that the HG/DOX/ADSC^FGF21 hydrogel significantly enhanced the proliferation and tube formation of HUVECs, promoted M2 macrophage polarization, and reduced the ROS levels in cells. Especially, the HG/DOX/ADSC^FGF21 hydrogel improved the MRSA-infected burn wound healing by alleviating wound ROS and increasing the M2 macrophage ratio. RNA sequencing revealed that the HG/DOX/ADSC^FGF21 hydrogel activated the MAPK and SIRT1 signaling pathways, which may promote neovascularization and collagen deposition. The study demonstrates that the HG/DOX/ADSC^FGF21 hydrogel may serve as a promising candidate for treating infected burn wounds.