Inhalable CAR-T cell-derived exosomes as paclitaxel carriers for treating lung cancer

Abstract

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-γ and TNF-α 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.

Maximizing Oxaliplatin's Impact on EGFR+ Colorectal Cancer Through Targeted Extracellular Vesicles

“…Paclitaxel was encapsulated in these CAR-Exos (PTX@CAR-Exos) and administered to lung cancer mouse models through inhalation. The results showed that inhaled PTX@CAR-Exos accumulated within the tumor area and signi cantly reduced tumor size, extended survival time, and exhibited lower toxicity [25][26][27][28]. Rezakhani et al's study used various EVs loaded with doxorubicin and paclitaxel to treat different types of cancer.…”

Targeted exosome-based nanoplatform for new-generation therapeutic strategies

“…Exosomes have inherent biochemical characteristics that contribute to their extensive application in drug-delivery systems (figure 3). Exosomes can be loaded with different cargoes, including proteins, genetic substances (miRNA and siRNA), and drug molecules (doxorubicin, paclitaxel, methotrexate, and curcumin), using physical, chemical, or biological methods [115][116][117][118][119][120].…”

Fusion of Exosomes and Nanotechnology: Cutting-Edge Cancer Theranostics

“…151 In cancer treatment, CAR T-cell-derived exosomes are an effective solution. 152,153 Modified exosomes, artificial exosomes, and chimeric exosomes are frontiers of exosomesbased translational medicine, and these types of exosomes show effective antitumor activity. 154−156 Engineered exosomes developed after modifications in surface and inner cargo level is effective on anticancer activity.…”

“…This method is limited in life-threatening toxicity, but the most exciting fact is CAR T-cell-derived exosomes are less toxic compared to CAR-T therapy . In cancer treatment, CAR T-cell-derived exosomes are an effective solution. , Modified exosomes, artificial exosomes, and chimeric exosomes are frontiers of exosomes-based translational medicine, and these types of exosomes show effective antitumor activity. − Engineered exosomes developed after modifications in surface and inner cargo level is effective on anticancer activity. − Modified exosomes have now become the leading approach in exosomes-based cancer therapy.…”