PDF(Pubmed)
Abstract：
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.
摘要：
小的细胞外囊泡(sEV)已经成为有希望的治疗剂和药物递送载体。使用遗传修饰策略对sEV及其内容进行有针对性的修饰是最流行的方法之一。这项研究调查了p53与含抑制蛋白结构域的蛋白1（ARRDC1）和CD63融合对sEV产生的影响。p53加载效率，和治疗效果。ARRDC1-p53（ARP）或CD63-p53（CDP）的过表达显着提高了p53的mRNA和蛋白质水平。ARRDC1和CD63的掺入显着增强了HEK293T-sEV的生物发生，sEV相关蛋白TSG101和LAMP1的显着增加证明，导致sEV产生的增加。重要的是,与ARRDC1或CD63融合可显著提高p53融合蛋白及其mRNA加载到sEV的效率.配备ARP或CDP的sEV显着增强p53融合蛋白和mRNA在p53-nullH1299细胞中的富集，导致细胞凋亡明显增加和细胞增殖减少，ARP-sEV比CDP-sEV更有效。这些发现强调了ARRDC1-和CD63修饰的sEV的功能增强，强调基因修饰在基于sEV的靶向癌症治疗疗法中的潜力。
