Biodegradable Carrier-Free Nanomedicine via Self-Assembly of Pure Drug Molecules for Triple Sensitization of Radiotherapy.

Radiotherapy (RT) has been one of the most widely applied cancer treatments, while radiotherapy resistance remains a major limitation. Herein, we synthesized a biodegradable AID nanomedicine incorporating atovaquone (ATO), new indocyanine green (IR820), and doxorubicin (DOX) via π-π stacking and hydrophobic interactions, along with high drug loading efficiency and long-term stability. The AID nanomedicine effectively reduces the activity of mitochondrial electron transport chain complexes I/II/III/IV/V, disrupts the mitochondrial oxidative respiratory chain, and decreases oxygen consumption, thereby alleviating the hypoxic microenvironment within the tumor. Moreover, mild hyperthermia induced by IR820 improves intratumor blood flow, thereby enhancing the radiotherapeutic efficiency. Additionally, DOX-triggered chemotherapy further sensitizes the tumor to radiotherapy, achieving triple sensitization. Our findings demonstrate that AID nanomedicine, combined with near-infrared (NIR) and radiotherapy, significantly suppresses tumor growth in vivo without noticeable side effects. In conclusion, our work presents a self-assembling nanomedicine with excellent biocompatibility, showing great potential for future development in triple radiotherapy sensitization.