Intracellular Delivery of P311 Protein and Scavenge of ROS by Targeting Liposome Promote Fibroblast Differentiation to Myofibroblast and Diabetic Wound Healing via Regulating the GDF-15 Pathway

Delayed wound healing remains a major complication of diabetes and places a heavy burden on global health. Excessive oxidative stress in the local microenvironment impairs wound repair and diminishes therapeutic efficacy. We developed P311-Ox@Lipo-R8, a dual-function platform combining R8-modified liposomes with P311 protein and oxidation-functionalized β-cyclodextrins (Ox-β-CD), which simultaneously facilitates intracellular protein delivery and reactive oxygen species (ROS) scavenging. The R8-conjugated liposomes effectively transported both P311 and Ox-β-CD into cells. P311-Ox@Lipo-R8 showed strong ROS scavenging ability in vitro. Furthermore, P311-Ox@Lipo-R8 promotes the differentiation of fibroblasts into myofibroblasts and improves cell contractile ability. P311-Ox@Lipo-R8 could accelerate granulation tissue formation, collagen deposition, and diabetic wound healing in vivo. RNA-sequencing analysis showed that P311-Ox@Lipo-R8 could activate the GDF-15 pathway. These findings establish that targeted liposomal delivery of P311 combined with ROS clearance promotes fibroblast differentiation to myofibroblast and wound healing through GDF-15 regulation, offering a potential therapeutic strategy for diabetic wounds.