肿瘤细胞治疗研究
英文原题：Inhalable CAR-T cell-derived exosomes as paclitaxel carriers for treating lung cancer.
我们的研究提供了一种基于纳米囊泡的递送平台，以提高化疗药物的疗效并减少副作用。这一新策略可能改善目前肺癌临床治疗所面临的障碍。
非小细胞肺癌（NSCLC）是全球性的健康威胁，年发病率和死亡率均较高。紫杉醇（PTX）等化疗药物已在临床上广泛应用。然而，PTX非特异性循环导致的全身毒性常引起多器官损伤，包括肝脏和肾脏。因此，有必要开发一种新策略以增强PTX的靶向抗肿瘤效果。
在此，我们工程化改造了表达嵌合抗原受体（CAR-Exos）的T细胞来源的外泌体，其通过CAR-Exos的抗MSLN单链可变片段（scFv）靶向表达间皮素（MSLN）的Lewis肺癌（MSLN-LLC）。将PTX封装入CAR-Exos（PTX@CAR-Exos），并通过吸入给药至原位肺癌小鼠模型。
吸入型PTX@CAR-Exos在肿瘤区域蓄积，缩小肿瘤体积，并延长生存期且毒性较小。此外，PTX@CAR-Exos重编程了肿瘤微环境并逆转了免疫抑制，这归因于浸润的CD8+ T细胞以及IFN-和TNF-水平升高。
BACKGROUND: Non-small cell lung cancer (NSCLC) is a worldwide health threat with high annual morbidity and mortality. Chemotherapeutic drugs such as paclitaxel (PTX) have been widely applied clinically. However, systemic toxicity due to the non-specific circulation of PTX often leads to multi-organ damage, including to the liver and kidney. Thus, it is necessary to develop a novel strategy to enhance the targeted antitumor effects of PTX. METHODS: Here, we engineered exosomes derived from T cells expressing the chimeric antigen receptor (CAR-Exos), which targeted mesothelin (MSLN)-expressing Lewis lung cancer (MSLN-LLC) through the anti-MSLN single-chain variable fragment (scFv) of CAR-Exos. PTX was encapsulated into CAR-Exos (PTX@CAR-Exos) and administered via inhalation to an orthotopic lung cancer mouse model. RESULTS: Inhaled PTX@CAR-Exos accumulated within the tumor area, reduced tumor size, and prolonged survival with little toxicity. In addition, PTX@CAR-Exos reprogrammed the tumor microenvironment and reversed the immunosuppression, which was attributed to infiltrating CD8 + T cells and elevated IFN- and TNF- levels. CONCLUSIONS: Our study provides a nanovesicle-based delivery platform to promote the efficacy of chemotherapeutic drugs with fewer side effects. This novel strategy may ameliorate the present obstacles to the clinical treatment of lung cancer.
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