Development of Extracellular Vesicle Therapeutics: Challenges, Considerations, and Opportunities

Abstract

Extracellular vesicles (EVs) hold great promise as therapeutic modalities due to their endogenous characteristics, however, further bioengineering refinement is required to address clinical and commercial limitations. Clinical applications of EV-based therapeutics are being trialed in immunomodulation, tissue regeneration and recovery, and as delivery vectors for combination therapies. Native/biological EVs possess diverse endogenous properties that offer stability and facilitate crossing of biological barriers for delivery of molecular cargo to cells, acting as a form of intercellular communication to regulate function and phenotype. Moreover, EVs are important components of paracrine signaling in stem/progenitor cell-based therapies, are employed as standalone therapies, and can be used as a drug delivery system. Despite remarkable utility of native/biological EVs, they can be improved using bio/engineering approaches to further therapeutic potential. EVs can be engineered to harbor specific pharmaceutical content, enhance their stability, and modify surface epitopes for improved tropism and targeting to cells and tissues in vivo. Limitations currently challenging the full realization of their therapeutic utility include scalability and standardization of generation, molecular characterization for design and regulation, therapeutic potency assessment, and targeted delivery. The fields’ utilization of advanced technologies (imaging, quantitative analyses, multi-omics, labeling/live-cell reporters), and utility of biocompatible natural sources for producing EVs (plants, bacteria, milk) will play an important role in overcoming these limitations. Advancements in EV engineering methodologies and design will facilitate the development of EV-based therapeutics, revolutionizing the current pharmaceutical landscape.

Effect of 2D and 3D Culture Microenvironments on Mesenchymal Stem Cell-Derived Extracellular Vesicles Potencies

“…EVs, in contrast, have no vascular obstructive effect or apparent adverse effects. These properties suggest that EVs could be safely and easily used in therapies such as for respiratory diseases ( Abreu et al, 2016 ; Fujita et al, 2018 ; Claridge et al, 2021a ).…”

“…These are mediated by the secretion of various cytokines and soluble factors, which in turn modulate immune cell activity and promote tissue generation. More recently, MSC-derived extracellular vesicles (EVs) have also attracted attention as therapeutic products produced by MSCs which may have potential use in tissue repair and regeneration ( Baglio et al, 2012 ; György et al, 2015 ; Chen et al, 2017 ; Claridge et al, 2021a ).…”

SKP-SC-EVs Mitigate Denervated Muscle Atrophy by Inhibiting Oxidative Stress and Inflammation and Improving Microcirculation

“…Maintaining the homeostasis of the regenerative microenvironment is essential for muscle growth and development. Based on the EVs delivery system, we constructed an endogenous beneficial microenvironment and activated the protection mechanism underpinning tissue regeneration, which is a promising method [ 61 , 62 ]. Increasing evidence has shown that EVs actively regulate angiogenesis in vascular endothelial cells by acting on blood vessel formation [ 63 ].…”

Advances in the Application of Exosomes Identification Using Surface-Enhanced Raman Spectroscopy for the Early Detection of Cancers

“…Under physiological and pathological conditions, exosomes can be actively secreted extracellularly by various cells including immune cells, stem cells and tumor cells, and can transport a large number of biomolecules from the parent cell to other cells, which is closely related to the pathogenesis of tumors ( Claridge et al, 2021 ; Oey et al, 2021 ; Yamada, 2021 ). Because of their small size, exosomes are able to avoid phagocytosis by mononuclear macrophages and cross the vascular wall to the extracellular matrix, they are widely present in various body fluids including blood, saliva, urine, cerebrospinal fluid, and thoracoabdominal fluid ( Clark et al, 2021 ; Leggio et al, 2021 ; Mao et al, 2021 ; Prieto-Vila et al, 2021 ).…”