Researchers engineer inhalable CAR-T cell-derived exosomes as paclitaxel carriers for treating lung cancer

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.

Researchers at Sun Yat-Sen University have 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. 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-γ and TNF-α levels.

Schematic illustration of inhalable CAR exosomes derived from
CAR-T cells as PTX carriers for treating lung cancer

Scheme 1.

A Preparation process of PTX@CAR-Exo. B Antitumor effect of inhalable PTX@CAR-Exo against lung cancer. CAR-T cell-derived exosomes (CAR-Exos) inherited the targeted cytolytic effects from parental cells by releasing granzyme B and perforins. The loaded PTX was delivered into the tumor area to stimulate immune responses. In contrast to conventional CAR-T cell therapy and intravenous administration of PTX, the inhalable PTX@CAR-Exos used in an orthotopic lung cancer model exhibited superior antitumor effects and improved the bioavailability of both CAR-Exos and PTX, with decreased systemic toxicity

This 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.

Zheng W, Zhu T, Tang L, Li Z, Jiang G, Huang X. (2023) Inhalable CAR-T cell-derived exosomes as paclitaxel carriers for treating lung cancer. J Transl Med 21(1):383. [article]

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