Multibiofunctional TFEB-engineered endothelial progenitor cell-derived extracellular vesicles/hydrogel system for rescuing critical limb ischemia

Critical limb ischemia (CLI) is the terminal stage of peripheral arterial disease (PAD), always leading to a high risk of amputations and deaths. While the majority of strategies only focus on recanalization of patients, these methods are unsatisfactory due to limited therapeutic effect and surgical damage. Herein, a multifunctional engineered-extracellular vesicles (EVs)/hydrogel system is designed for facilitating angiogenesis and protecting the ischemic muscle tissue via a non-surgical delivery strategy. The EVs released from endothelial progenitor cells (EPCs), an emerging stem cell therapy candidate, were used to play the pro-angiogenesis role. Transcription factor EB (TFEB), a master regulator of autophagy, was utilized to genetically modify the EVs for building TFEB-engineered EVs (TFEB-EVs) to reduce the impairment of muscle. Moreover, a thermal-/pH-responsive hydrogel (FPD), prepared by F127, polyethylenimine (PEI), and oxidized dextran, served as a sensitive controlled-release carrier and improved the stability of TFEB-EVs in vivo , simultaneously. Our results exhibited that TFEB-EVs/FPD significantly strengthened neovascularization, alleviated muscle damage, and protected the limb function of CLI mice. Overall, TFEB-EVs/FPD offered a convenient, safe, and non-surgical approach for rescuing CLI.