Specific generation of nitric oxide in mitochondria of cancer cell for selective oncotherapy

Nitric oxide (NO) gas therapy, especially, L-arginine (L-Arg)-based NO treatment strategies have attracted extensive attention in the field of oncotherapy. However, current strategies are unable to differentiate well between normal cells and cancer cells, which may lead to unpredictable toxicity. Motivated by the fact that mitochondria of cancer cells can express excessive nitric oxide synthetase (NOS), herein, a nanozyme-based NO generator, cerium oxide (CeO₂)-AT, is fabricated to specifically catalyze the production of NO in cancer cells for selective tumor treatment. In this system, after being endocytosed into cancer cells, the generator can produce a number of NO under the catalysis of NOS in mitochondria of cancer cells, which can disrupt the mitochondrial respiratory chain of tumor cells and further induce cell apoptosis. In addition, the generator with catalase (CAT)-like activity can catalyze H₂O₂ to produce O₂, which can promote the generation of NO and improve the performance of NO gas therapy. What is more, our system has no obvious impact on the viability of normal cells owing to the less production of NO. Our work paves a new way for the development of highly selective NO-based treatment particularly useful for the safe and specific cancer therapy.