Reversing lung cancer radioresistance by hyperpermeable tellurium nanotherapeutics via remodeling tumor microenvironment

Tolerance to radiotherapy is the main cause of radiotherapy failure in patients with lung cancer. The key to successful treatment is to find effective targets and signaling pathways to reverse radioresistance. Based on the importance of the epidermal growth factor receptor (EGFR) signaling pathway and mitochondria in lung cancer, we developed an EGFR/mitochondrial dual-targeting radiosensitizer ([email protected]) based on tellurium nanostars to overcome radioresistance in lung cancer. The as-prepared [email protected] nanosystem successfully located in the mitochondria not only increased the accumulation and penetration of the Te nanosystem in radiotherapy-tolerant lung cancer cells but also enhanced the sensitivity of A549 cells to X-rays, leading to excellent anticancer efficacy via overproduction of reactive oxygen species and mitochondrial dysfunction. Consistently, using unilateral and bilateral tumor models, we confirmed that [email protected] combined with X-ray irradiation had a high therapeutic effect and could reshape the tumor immune microenvironment by affecting the infiltration of some specific immune cells, such as M2 macrophages and natural killer cells. Taken together, our study highlights a facile design strategy for Te-based nanoradiosensitizers to reverse the radiation resistance of lung cancer. Furthermore, the findings provide novel insights into their application in theranostics in cancer medicine.