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- Title
Fusion with ARRDC1 or CD63: A Strategy to Enhance p53 Loading into Extracellular Vesicles for Tumor Suppression.
- Authors
Liu, Min; Zhang, Yu; He, Jianfeng; Liu, Wanxi; Li, Zhexuan; Zhang, Yiti; Gu, Ao; Zhao, Mingri; Liu, Mujun; Liu, Xionghao
- Abstract
Simple Summary: This study investigates the potential of small extracellular vesicles (sEVs) as vehicles for delivering therapeutic agents, with a focus on the p53 tumor suppressor gene. Fusion with CD63 or ARRDC1 was found to facilitate the overexpression and proper localization of p53 and significantly increase the yield and loading efficiency of sEVs with p53 mRNA and proteins. Moreover, the functional assessment of these engineered sEVs on H1299 cells demonstrated an enhanced anti-tumor effect, particularly with ARP-sEVs, suggesting a superior inhibition of cell proliferation and promotion of apoptosis. These results are expected to be informative in the application of EV therapy. Small extracellular vesicles (sEVs) have emerged as promising therapeutic agents and drug delivery vehicles. Targeted modification of sEVs and their contents using genetic modification strategies is one of the most popular methods. This study investigated the effects of p53 fusion with arrestin domain-containing protein 1 (ARRDC1) and CD63 on the generation of sEVs, p53 loading efficiency, and therapeutic efficacy. Overexpression of either ARRDC1–p53 (ARP) or CD63–p53 (CDP) significantly elevated p53 mRNA and protein levels. The incorporation of ARRDC1 and CD63 significantly enhanced HEK293T-sEV biogenesis, evidenced by significant increases in sEV-associated proteins TSG101 and LAMP1, resulting in a boost in sEV production. Importantly, fusion with ARRDC1 or CD63 substantially increased the efficiency of loading both p53 fusion proteins and its mRNA into sEVs. sEVs equipped with ARP or CDP significantly enhanced the enrichment of p53 fusion proteins and mRNA in p53-null H1299 cells, resulting in a marked increase in apoptosis and a reduction in cell proliferation, with ARP-sEVs demonstrating greater effectiveness than CDP-sEVs. These findings underscore the enhanced functionality of ARRDC1- and CD63-modified sEVs, emphasizing the potential of genetic modifications in sEV-based therapies for targeted cancer treatment.
- Subjects
EXTRACELLULAR vesicles; P53 antioncogene; TUMOR suppressor genes; P53 protein; CHIMERIC proteins; POLYMERSOMES
- Publication
Biomolecules (2218-273X), 2024, Vol 14, Issue 5, p591
- ISSN
2218-273X
- Publication type
Article
- DOI
10.3390/biom14050591