Native and bioengineered extracellular vesicles for cardiovascular therapeutics

Extracellular vesicles (EVs) are a heterogeneous group of natural particles that are relevant to the treatment of cardiovascular diseases. These endogenous vesicles have certain properties that allow them to survive in the extracellular space, bypass biological barriers and deliver their biologically active molecular cargo to recipient cells. Moreover, EVs can be bioengineered to increase their stability, bioactivity, presentation to acceptor cells and capacity for on-target binding at both cell-type-specific and tissue-specific levels. Bioengineering of EVs involves the modification of the donor cell before EV isolation or direct modification of the EV properties after isolation. The therapeutic potential of native EVs and bioengineered EVs has been only minimally explored in the context of cardiovascular diseases. Efforts to harness the therapeutic potential of EVs will require innovative approaches and a comprehensive integration of knowledge gathered from decades of research into molecular-compound delivery. In this Review, we outline the endogenous properties of EVs that make them natural delivery agents as well as the features that can be improved by bioengineering. We also discuss the therapeutic applications of native and bioengineered EVs to cardiovascular diseases and examine the opportunities and challenges that need to be addressed to advance this research area, with an emphasis on clinical translation. Extracellular vesicles are a heterogeneous group of natural particles that can deliver their biologically active molecular cargo to recipient cells. In this Review, the authors outline the endogenous properties of extracellular vesicles that make them natural delivery agents and the features that can be improved by bioengineering for the treatment of cardiovascular diseases. Key points Extracellular vesicles (EVs) secreted from stem or progenitor cells and from differentiated somatic cells have regenerative properties in the context of myocardial infarction, ischaemic limb disease and stroke. Despite the benefits of native EVs as delivery agents, their application in the cardiovascular context is hindered by intrinsic drawbacks, such as their undefined and heterogeneous nature and limited tropism. EVs can be improved by bioengineering approaches using both pre-isolation and post-isolation methods to increase the targeting, bioactivity, kinetics, biodistribution and contents of EVs. Bioengineering of EVs is necessary to improve their clinical pot