Engineered mammalian and bacterial extracellular vesicles as promising nanocarriers for targeted therapy

Abstract

Extracellular vesicles (EVs), which are nanocarriers with phospholipid bilayer structures released by most cells, play a key role in regulating physiological and pathological processes. EVs have been investigated due to their loading capacity, low toxicity, immunogenicity, and biofunctions. Although EVs have shown good potential as therapeutic vehicles, natural EVs have a poor targeting ability, which substantially reduces the therapeutic effect. Through the addition of a targeting unit into the membrane surface of EVs or inside EVs by engineering technology, the therapeutic agent can accumulate in specific cells and tissues. Here, we focus on mammalian EVs (MEVs) and bacterial EVs (BEVs), which are the two most common types of EVs in the biomedical field. In this review, we describe engineered MEVs and BEVs as promising nanocarriers for targeted therapy and summarize the biogenesis, isolation, and characterization of MEVs and BEVs. We then describe engineering techniques for enhancement of the targeting ability of EVs. Moreover, we focus on the applications of engineered MEVs and BEVs in targeted therapy, including the treatment of cancer and brain and bone disease. We believe that this review will help improve the understanding of engineered MEVs and BEVs, thereby promoting their application and clinical translation.

Keywords: Biological engineering; bacterial extracellular vesicles; chemical modification; mammalian extracellular vesicles; targeted therapy.

Figure 1

The biogenesis of mammalian extracellular vesicles (MEVs) and bacterial extracellular vesicles (BEVs). (A) The biogenesis of MEVs. (B) The biogenesis of BEVs. Figures were created with Biorender.com.

Figure 2

The isolation of MEVs and BEVs. (A) The isolation of MEVs. (B) The isolation of BEVs. Figures were created with Biorender.com.

Figure 3

(A) The procedure to produce hybrid nanoparticles by membrane fusion. Liposomes with targeting molecules on the surface can be delivered into EVs through membrane fusion^[79]. Copyright 2018 WILEY-VCH. (B) The procedure to produce hybrid nanoparticles by membrane coating^[80]. Copyright 2020 Ivyspring International Publisher. (C) The fusion of the targeting peptide with LAMP-2B^[66]. Copyright 2021 Ivyspring International Publisher. (D) The fusion of the delivery molecule with CD63^[81]. Copyright 2018 Springer Nature. (E) Targeted modification of EVs based on chemical covalent reactions^[82]. Copyright 2021 Elsevier. (F) Targeted modification of EVs based on chemical non-covalent reactions^[82]. Copyright 2021 Elsevier. LAMP-2B: Lysosome-associated membrane glycoprotein 2B.

Figure 4

The application of engineered MEVs and BEVs in targeted therapy. The figure was created with Biorender.com. MEVs: Mammalian extracellular vesicles; BEVs: bacterial extracellular vesicles.

Figure 5

(A) Engineered MEVs for tumor chemotherapy. Schematic illustration of the construction and delivery of doxorubicin loaded in MEVs, which show tumor targeting and antitumor effects^[89]. Copyright 2016 American Chemical Society. (B) Engineered BEVs for tumor gene therapy. Schematic illustration of the construction and delivery of siRNA loaded in BEVs, which show tumor targeting and antitumor effects^[20]. Copyright 2014 American Chemical Society. (C) Engineered MEVs for tumor photothermal therapy^[15]. Schematic illustration of the construction of BEV-Mel, which shows tumor targeting and antitumor effects. Copyright 2019 Springer Nature. (D) Engineered MEVs for tumor immunotherapy^[119]. Schematic illustration of the construction of SMART-MEVs, which show tumor targeting and antitumor effects. Copyright 2020 Elsevier. MEVs: Mammalian extracellular vesicles; BEVs: bacterial extracellular vesicles; SMART-MEVs: synthetic multivalent antibodies retargeted MEVs. Significance of finding was defined as follows: not significant, ^nsP > 0.05; ^*P < 0.05; ^**P < 0.01; ^***P < 0.001.

Figure 6

(A) Engineered MEVs for AD. Schematic illustration of the construction of MEVs to deliver BACE1 mRNA with targeting and anti-AD effects^[83]. Copyright 2011 Springer Nature. (B) Engineered MEVs for PD. Schematic illustration of the construction of MEVs to deliver catalase mRNA with targeting and anti-PD effects^[81]. Copyright 2018 Springer Nature. (C) Engineered MEVs for ischemic stroke.Schematic illustration of the construction of MEVs to deliver catalase miR-124 with targeting and anti-ischemic stroke effects^[124]. Copyright 2017 Elsevier. MEVs: Mammalian extracellular vesicles. AD: Alzheimer’s disease. PD: Parkinson’s disease. Significance of finding was defined as follows: not significant, ^nsP > 0.05; ^*P < 0.05; ^**P < 0.01; ^***P < 0.001.

Figure 7

(A) Engineered MEVs for OA. Schematic illustration of the construction of MEVs to deliver KGN with targeting and anti-OA effects^[71]. Copyright 2021 Springer Nature. (B) Engineered MEVs for OP. Schematic illustration of the construction of hybrid nanoparticles to deliver antagomir-188 with targeting and anti-OP effects^[18]. Copyright 2021 Elsevier. MEVs: Mammalian extracellular vesicles; OA: osteoarthritis; KGN: kartogenin; OP: osteoporosis. Significance of finding was defined as follows: not significant, ^nsP > 0.05; ***P < 0.0001.