A biomimetic nanotherapeutic hydrogel orchestrates multi-mechanism therapy for ischemic skin flaps

Despite considerable advances in nanotherapeutics, their clinical application is often limited by suboptimal monotherapy, rapid immune clearance and insufficient target-site accumulation. These limitations are particularly pronounced in the treatment of flap necrosis because of the complex ischemic microenvironment. To address this challenge, we fabricated a multifunctional therapeutic platform by loading melanin nanoparticles (MNPs) with the PI3Kα agonist UCL-TRO-1938, coating them with membranes derived from tert-butyl hydroperoxide (TBHP)-preconditioned human umbilical vein endothelial cells (HUVECs), and embedding them within a fibrin hydrogel. The resulting CM-1938@MNP hydrogels conferred cytoprotective effects in vitro by rescuing HUVECs from TBHP induced dysfunction and shifting macrophage polarization from the M1 to M2 phenotype. In a mouse model of ischemic skin flaps, local injection of the hydrogel markedly improved flap survival by stimulating angiogenesis, alleviating oxidative stress, and suppressing inflammation; these results were confirmed by RNA-seq analysis. This work presents a biomimetic strategy that transcends conventional single target therapies, offering a promising versatile platform for treating ischemia.