Native and bioengineered extracellular vesicles for cardiovascular therapeutics

Abstract

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.

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 potential for cardiovascular applications.

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Fig. 1: Limitations and challenges in the use of native EVs as cardiovascular therapies.
Fig. 2: Modulation of EVs for cardiovascular therapies.
Fig. 3: Examples of EV-modulation strategies for cardiac therapies.

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Acknowledgements

The authors were supported by the Portuguese National Funding Agency for Science, Research and Technology (fellowship to R.C.d.A. (SFRH/SFRH/BD/129317/2017) and Project Exo-Heart (POCI-01-0145-FEDER-029919) to H.F.). P.A.d.C.M. is funded by a Dutch Heart Foundation grant (NHS2015T066). P.A.d.C.M., C.E. and L.F. are members of the EEU COST Action CardioRNA CA17129. S.S. has received grants from the NIH (HL124187, HL140469, HL148786 and NYSTEM C32562GG) and Transatlantic Foundation Leducq. C.E. has received funding via a British Heart Foundation (BHF) programme grant, personal Chair awards (RG/15/5/31446 and CH/15/1/31199) and the BHF Centre of Vascular Regeneration. L.F. is supported by Program Interreg Atlantic Space through the European Fund for Regional Development (Project NeuroAtlantic (EAPA_791/2018) and Project 2IQBIONEURO (0624_2IQBIONEURO_6_E)) and EC Project ERAatUC (669088).

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Correspondence to Lino Ferreira.

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Glossary

Macropinocytosis

A regulated form of endocytosis that mediates non-selective uptake of extracellular material, such as soluble molecules, nutrients and antigens.

Electroporation

A transfection method in which biological membranes are permeabilized by exposure to an electrical pulse.

Heat–shock

A transformation technique that relies on heat to induce membrane permeabilization.

Sonication

The use of ultrasound technology to physically disrupt biological membranes and facilitate the entry of exogenous compounds.

Passive loading

A strategy that relies on passive diffusion or complexation of a molecule with a cell or organelle; loading can be dependent on various factors, such as pH, osmotic pressure, electric charge and hydrophobicity.

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de Abreu, R.C., Fernandes, H., da Costa Martins, P.A. et al. Native and bioengineered extracellular vesicles for cardiovascular therapeutics. Nat Rev Cardiol (2020). https://doi.org/10.1038/s41569-020-0389-5

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