Abstract
Precise, noninvasive targeting and controlled drug release to the nervous system could transform both basic research and clinical therapy. In this work, we developed a focused ultrasound-responsive delivery system based on extracellular vesicles (EVs), which are naturally occurring and biocompatible phospholipid nanocarriers. To enable the ultrasound responsiveness, a lipid-gas phase transition material Perfluoropentane (PFP) was co-encapsulated with therapeutic agents into EVs via low-temperature sonication. The resulting EVs had a size of 100-200 nm and demonstrated efficient, on-demand release upon ultrasound stimulation. In primary cultured neurons, EVs loaded with lidocaine successfully suppressed calcium activity and showed minimum cytotoxicity. Finally, we demonstrated in vivo application of this system for modulation pain sensitivity in rats. Our EVs-drugs platform demonstrated a safe, and ultrasound-activated drug delivery with high spatiotemporal control, showing strong potential therapeutic applications.