https://orcid.org/0000-0002-2797-1099
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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.
Abbreviations
MSCs, Mesenchymal stem cells; P-ENVs, Platelet membrane-coated exosome-mimetic nanovesicles; ENVs, Exosome-mimetic nanovesicles; TEM, Transmission electron microscopy; NTA, Nanoparticle tracking analysis; IVIS, In vivo imaging system; ORO, Oil Red O; EVs, Extracellular vesicles; P-NPs, Platelet membrane-coated nanoparticles; IMDM, Iscove’s modified dulbecco’s medium; VSMCs, Vascular smooth muscle cells; HSMCs, Human aortic smooth muscle cells; MVSMCs, Mouse aortic vascular smooth muscle cells; DMEM/F-12, Dulbecco’s modified eagle medium/nutrient mixture F-12; HUVECs, Human umbilical vein endothelial cells; DMEM, Dulbecco’s modified eagle medium; ECM, Endothelial cell medium; PBS, Phosphate buffered saline; EDTA, Ethylene diamine tetraacetic acid; PRP, Platelet rich plasma; PGE1, Prostaglandin E1; PEG, Polyethylene glycol; LPS, Lipopolysaccharide; FBS, Fetal bovine serum; OD, Optical density; GO, Gene ontology; KEGG, Kyoto encyclopedia of genes and genomes; vWF, von Willebrand factor; NBD, Nitrobenzoxadiazolyl; APOA-I, Apolipoprotein A-I; FI, Fluorescence intensity; HE, Hematoxylin-eosin; SD, Standard deviation; RES, Reticuloendothelial system; ICAM-1, Intracellular adhesion molecule-1; TG, Triglyceride; TC; Total cholesterol; LDL, Low-density lipoprotein; HDL, High-density lipoprotein; RBCs, Red blood cells; WBCs, White blood cells; PLTs, Platelets; HGB, Hemoglobin; CREA, Creatinine; BUN, Blood urea nitrogen; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; DPCs, Dermal papilla cells; SCI, Spinal cord injury; RCT, Reverse cholesterol transport.
Data Sharing Statement
The datasets used and analyzed during the current study are available from the corresponding author.
Ethics Approval and Informed Consent
The animal experiment was conducted under the approval and supervision of the Experimental Animals Ethics Committee of Fuwai Hospital (FW-2022-0027), and all procedures met the National Institutes of Health guidelines. All human experiments were performed in line with the Ethics Committee of Fuwai Hospital (FW-2020-1317) and followed the guidelines outlined in the Declaration of Helsinki. Besides, informed consent was obtained from the study participants.
Consent for Publication
All authors agree to publish this paper in this journal.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
None of the authors declare any conflicts of interest.