Targeted Delivery of Mesenchymal Stem Cell-Derived Bioinspired Exosome-Mimetic Nanovesicles with Platelet Membrane Fusion for Atherosclerotic Treatment

Int J Nanomedicine. 2024 Mar 13:19:2553-2571. doi: 10.2147/IJN.S452824. eCollection 2024.

Abstract

Purpose: Accumulating evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes hold significant potential for the treatment of atherosclerosis. However, large-scale production and organ-specific targeting of exosomes are still challenges for further clinical applications. This study aims to explore the targeted efficiency and therapeutic potential of biomimetic platelet membrane-coated exosome-mimetic nanovesicles (P-ENVs) in atherosclerosis.

Methods: To produce exosome-mimetic nanovesicles (ENVs), MSCs were successively extruded through polycarbonate porous membranes. P-ENVs were engineered by fusing MSC-derived ENVs with platelet membranes and characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. The stability and safety of P-ENVs were also assessed. The targeted efficacy of P-ENVs was evaluated using an in vivo imaging system (IVIS) spectrum imaging system and immunofluorescence. Histological analyses, Oil Red O (ORO) staining, and Western blot were used to investigate the anti-atherosclerotic effectiveness of P-ENVs.

Results: Both ENVs and P-ENVs exhibited similar characteristics to exosomes. Subsequent miRNA sequencing of P-ENVs revealed their potential to mitigate atherosclerosis by influencing biological processes related to cholesterol metabolism. In an ApoE-/- mice model, the intravenous administration of P-ENVs exhibited enhanced targeting of atherosclerotic plaques, resulting in a significant reduction in lipid deposition and necrotic core area. Our in vitro experiments showed that P-ENVs promoted cholesterol efflux and reduced total cholesterol content in foam cells. Further analysis revealed that P-ENVs attenuated intracellular cholesterol accumulation by upregulating the expression of the critical cholesterol transporters ABCA1 and ABCG1.

Conclusion: This study highlighted the potential of P-ENVs as a novel nano-drug delivery platform for enhancing drug delivery efficiency while concurrently mitigating adverse reactions in atherosclerotic therapy.

Keywords: atherosclerosis; biomimicry; exosome-mimetic nanovesicles; platelet membrane-coated nanovesicles; targeted delivery.

MeSH terms

  • Animals
  • Atherosclerosis* / drug therapy
  • Atherosclerosis* / metabolism
  • Biomimetics
  • Cholesterol / metabolism
  • Exosomes* / metabolism
  • Membrane Fusion
  • Mesenchymal Stem Cells* / metabolism
  • Mice

Substances

  • Cholesterol

Grants and funding

This work was supported by the National Key Research and Development Program of China (No: 2022YFC2009700, 2022YFC2009706), Natural Science Foundation of Beijing Municipality (No: 7222139), Foundation for Clinical and Translational Medical Research, Central Public Welfare Research of Chinese Academy of Medical Sciences (No: 2022-I2M-C&T-B-050), and Foundation for Clinical research of central high-level hospitals (No: 2023-GSP-GG-32).