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Review
. 2021 Dec:179:113910.
doi: 10.1016/j.addr.2021.113910. Epub 2021 Aug 3.

Extracellular vesicles as delivery systems at nano-/micro-scale

Peiwen Fu  1 , Jianguo Zhang  2 , Haitao Li  3 , Michael Mak  4 , Wenrong Xu  5 , Zhimin Tao  6
Affiliations
Review

Extracellular vesicles as delivery systems at nano-/micro-scale

Peiwen Fu et al. Adv Drug Deliv Rev. 2021 Dec.

Abstract

Extracellular vesicles (EVs) have shown significant promises as nano-/micro-size carriers in drug delivery and bioimaging. With more characteristics of EVs explored through tremendous research efforts, their unmatched physicochemical properties, biological features, and mechanical aspects make them unique vehicles, owning exceptional pharmacokinetics, circulatory metabolism and biodistribution pattern when delivering theranostic cargoes. In this review we firstly analyzed pros and cons of the EVs as a delivery platform. Secondly, compared to engineered nanoparticle delivery systems, such as biocompatible di-block co-polymers, rational design to improve EVs (exosomes in particular) were elaborated. Lastly, different pharmaceutical loading approaches into EVs were compared, reaching a conclusion on how to construct a clinically available and effective nano-/micro-carrier for a satisfactory medical mission.

Keywords: Drug delivery; Exosomes; Extracellular vesicles; Nanomaterials.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
Biogenesis and destination of EVs. Different types of EVs have distinct biogenic and disposal mechanisms as discussed in the text.
Figure 2.
Figure 2.
Structure, contents, and biophysical properties of exosomes. Exosomes have lipid bilayer membrane, heterogeneous components, highly expressed tetraspanin proteins (CD9, CD81, and CD63) on its surface, plentiful tetraspanin-associated proteins ICMAs, integrins and so forth. A large number of DNAs, RNAs, enzymes, and other functional proteins are encapsulated within.
Figure 3.
Figure 3.
(a-b) Schematic illustration regarding the EV transport through elastic matrix where the mesh size is smaller than the size of EVs. Aquaporin-1 expression on the EVs can increase its deformability. (c) AQP1-depleted EVs (AQP1) exhibited a significantly higher stiffness than control EVs (SCR). Reprinted with permission from Ref[39]. (d) Schematic representation of EVs’ mechanical properties measurement by atomic force microscopy (AFM). (e) A typical force-distance curve (FDCs) recorded on the EV surface and several common mechanical parameters related to the EV stiffness. Reprinted with permission from Ref[30]. (f) AFM image of RBC EVs. Reprinted with permission from Ref[56].
Figure 4.
Figure 4.
The life cycle of EVs during their tumor drug delivery. (a) EVs mainly accumulate in the liver, spleen, and kidney after injected into mice through the tail vein. CD47 expression on its surface helps resist phagocytosis by macrophages. (b) EVs penetrate through vascular endothelial cells via two routes: 1) deformability of EVs allows them to passively extravasate through the inter-endothelial fenestrae; 2) transcytosis is the active uptake of EVs by endothelial cells, then releasing cargo through exocytosis. ECM, extracellular matrix. (c) Cellular internalization of EVs via membrane fusion can directly release cargo.
Figure 5.
Figure 5.
(a) Schematic illustration of synthetic multivalent antibodies retargeted exosomes (SMART-Exos). (b) Confocal imaging of αCD3/αEGFR SMART-Exos (green) participating in cross-linking of MDA-MB-468 (red) and Jurkat (no fluorescent label) cells. A mixture of αCD3 SMART-Exos and αEGFR SMART-Exos was used as a control. Scale bars: 10 μm. (c) αCD3/αEGFR SMART-Exos can significantly inhibit tumor growth. Reprinted with permission from Ref[113]. (d-e) MSC-Exo loaded with phosphatase and tensin homolog small interfering RNA (PTEN-siRNA) enhanced axonal growth and elicited functional recovery. Reprinted with permission from Ref[178]. (f) In vitro erastin@FA-exo could delay drug release compared with free erastin in pH 7.4. (g-h) Erastin@FA-exo induced more apoptosis (Annexin V/7-AAD) and ferroptosis of MDA-MB-231 cell. Reprinted with permission from Ref[186].
Figure 6.
Figure 6.
The challenges for EVs en route to a next-generation drug delivery system.
See this image and copyright information in PMC

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