Tumor-targeted multifunctional extracellular vesicles as drug carriers for lung cancer therapy

Aim: Chemotherapy continues to be the frontline treatment for lung cancer patients. However, treatment-related toxicity and off-target effects limit the use of chemotherapy. Therefore, improvements in delivering chemotherapeutics with reduced toxicity to normal tissues are needed. In the present study, we combined nanotechnology with extracellular vesicle (EV) technology to produce tumor-targeted multifunctional EVs (tt-Mfn-EVs) as drug carriers for cancer therapy. Methods: The tt-Mfn-EVs were formulated by exogenously loading EVs with gold nanoparticles conjugated to cisplatin (CDDP) via pH-sensitive coordination ester linkage. Attached to the outer surface of drug-loaded EVs is the transferrin ligand for targeting transferrin receptor (TfR) overexpressing lung cancer cells. Results: The tt-Mfn-EVs were 138.2 nm in size and exhibited greater drug release kinetics at pH 5.5 compared to pH 7.2. They significantly reduced cell viability of A₅₄₉ (TfR high) lung cancer cells compared to HCC₈₂₇ (TfR low) cells and non-targeted EVs. Tt-Mfn-EVs also induced higher levels of apoptosis and DNA damage in A₅₄₉ and HCC₈₂₇ cells compared to control groups. Finally, tt-Mfn-EV-mediated cytotoxicity was minimal in normal human lung fibroblast (MRC-₉) and human embryonic kidney 293 (HEK₂₉₃) cells compared to free CDDP. Conclusion: Our study showed that tt-Mfn-EVs exerted selective and enhanced tumor-targeted cell killing in vitro, providing an opportunity for developing EV-based drug carriers for cancer therapy.