Abstract：
The clinical application of doxorubicin (DOX) is mainly restricted by its serious side effects, poor drug delivery efficiency, and limited immunogenic death (ICD) effect. To improve DOX-based chemotherapy and ameliorate its adverse effects, we utilized 3LL cell-derived extracellular vesicles to encapsulate DOX and sodium nitroprusside (SNP) to obtain DOX/SNP@CM, which could effectively target the tumor site by harnessing the inherent homologous targeting property of tumor cell membranes. DOX performed its role on chemotherapy, and SNP successfully respond to the intracellular GSH to continuously generate nitric oxide (NO). The in situ-produced NO upregulated the Fas expression on the tumor cell surface, thereby sensitizing the Fas/FasL pathway-mediated tumor cell apoptosis of DOX. Furthermore, NO also boosted the intratumoral infiltration of cytotoxic T cells by promoted ICD effect towards tumor cells. Importantly, the anti-tumor immunity tightly cooperated with Fas/FasL mediated tumor cell apoptosis by NO-mediated manipulation on Fas/FasL interaction, collectively making DOX/SNP@CM exert significant tumor growth inhibition with low-dose DOX. Remarkably, DOX and SNP both are widely used clinical medicines, ensuring DOX/SNP@CM a potential opportunity for future practical applications.
摘要：
多柔比星(DOX)的临床应用主要受到其严重副作用,药物输送效率差，和有限的免疫原性死亡（ICD）效应。改善基于DOX的化疗并改善其不良反应，我们利用3LL细胞来源的细胞外囊泡包裹DOX和硝普钠（SNP）以获得DOX/SNP@CM，通过利用肿瘤细胞膜固有的同源靶向特性，可以有效地靶向肿瘤部位。DOX在化疗中发挥了作用，SNP成功地响应细胞内GSH以持续产生一氧化氮(NO)。原位产生的NO上调肿瘤细胞表面Fas的表达,从而敏化了Fas/FasL通路介导的肿瘤细胞凋亡的DOX。此外，NO还通过促进ICD对肿瘤细胞的作用来促进细胞毒性T细胞的肿瘤内浸润。重要的是,通过NO介导的Fas/FasL相互作用的操纵，抗肿瘤免疫与Fas/FasL介导的肿瘤细胞凋亡紧密合作，共同使DOX/SNP@CM与低剂量DOX发挥显著的肿瘤生长抑制作用。值得注意的是,DOX和SNP都是临床上应用广泛的药物,确保DOX/SNP@CM成为未来实际应用的潜在机会。
