Therapeutic Applications of Stimuli-Based Release and Engineering of Extracellular Vesicles

Abstract

Extracellular vesicles (EVs), nano- to microsized lipid bilayer membrane-bound particles, are play an important role in intercellular communication and hold promise for drug delivery systems (DDSs). Their unique morphology and customizable attributes position EVs as innovative platforms for diagnostic and therapeutic applications. As DDSs, EVs should ensure precise, sustained, and targeted delivery to improve therapeutic efficacy. Thus, stimulus-responsive strategies, using endogenous (e.g., pH, hypoxia) and exogenous triggers (e.g., light, ultrasound), are currently being explored as promising strategies to achieve controlled drug release and enhanced targeting. For example, functionalizing EVs with chemical groups can enhance responsiveness, targeting, and imaging contrast. This review examines how various stimuli can be used to affect EV release, cargo loading, cell uptake, and targeting capabilities, which are crucial for advancing nanomedicine. Characterizing the impact of stimuli on EV release from cells provides essential insights into the cellular mechanisms and signaling pathways, and designing strategies to modulate EV release, aiding in developing advanced DDS, potentially minimizing side effects and enhancing targeted and sustained payload release. In sum, the review covers studies on stimulus-responsive EVs, both intrinsic and extrinsic, dual and hybrid EVs, and their therapeutic applications, elucidating the potential of engineered EVs in nanomedicine.