Extracellular Vesicles as an Efficient and Versatile System for Drug Delivery

Abstract

Despite the recent advances in drug development, the majority of novel therapeutics have not been successfully translated into clinical applications. One of the major factors hindering their clinical translation is the lack of a safe, non-immunogenic delivery system with high target specificity upon systemic administration. In this respect, extracellular vesicles (EVs), as natural carriers of bioactive cargo, have emerged as a promising solution and can be further modified to improve their therapeutic efficacy. In this review, we provide an overview of the biogenesis pathways, biochemical features, and isolation methods of EVs with an emphasis on their many intrinsic properties that make them desirable as drug carriers. We then describe in detail the current advances in EV therapeutics, focusing on how EVs can be engineered to achieve improved target specificity, better circulation kinetics, and efficient encapsulation of therapeutic payloads. We also identify the challenges and obstacles ahead for clinical translation and provide an outlook on the future perspective of EV-based therapeutics.

Keywords: clinical; drug delivery; extracellular vesicles; therapeutic; translation.

Figure 1

Biogenesis of extracellular vesicle (EV) subtypes, termed exosomes, microvesicles and apoptotic bodies. Exosomes are intraluminal vesicles which are released when a multivesicular body fuses with the cell membrane through exocytosis. Microvesicles are formed by outward shedding of the cell membrane into extracellular space. Apoptotic bodies are generated when cells undergo apoptosis. Figure was generated with BioRender.

Figure 2

Summary of modifications used to increase therapeutic efficacy of EV-based therapeutics. (1) Incorporation of various targeting moieties (nanobodies, bispecific antibodies, peptides) to target specific antigens on target cells or glycan groups/ligands that can bind to receptors on target cells. (2) Addition of CD47, PEG or removal of sialic acid to reduce clearance by macrophages of the RES. (3) Encapsulation of nucleic acids (plasmid DNA, mRNA, miRNA, siRNA), therapeutic proteins and small molecule drugs which are then delivered to target cells to carry out their therapeutic effects. Figure was created with Biorender.