Exogenous cargo-loaded extracellular vesicles as therapeutics: A review of pre-clinical studies

Once cast aside and overlooked, extracellular vesicles (EVs) were long believed to be mere vesicles carrying cellular waste. Although identified four decades ago, only in recent years have EVs gained global recognition for their potential as innovative therapeutic and diagnostic agents. These natural lipid nanoparticles are capable of being exogenously loaded with a wide range of therapeutic cargo. Endogenous origin confers biocompatibility, while nanoscale size enables EVs to overcome the various biological barriers with ease, making them a promising drug delivery platform that can be harnessed for the treatment of several disease conditions. Moreover, the components present on the EV surface can be modified for enhanced loading to achieve a more precise targeted cargo delivery. This comprehensive review summarizes the current literature on exogenously cargo-loaded EVs, including their exogenous loading methods, targeting mechanisms, intracellular delivery, clinical translation, biodistribution, and in vivo visualization. The review also discusses preclinical studies utilizing cargo-loaded EVs for treating various disease conditions, while highlighting the commonly encountered clinical and regulatory hurdles in the successful translation of exogenous cargo-loaded EV-based therapeutics.