Biomimetic nanoreactor of catalase and nitric oxide enhance peroxynitrite generation for radiosensitization

The redundant DNA-repairing capacity and robust hypoxia in tumors pose significant challenges of cancer radiotherapy. Herein, an amphiphilic nitric oxide (NO)-supplying conjugate (PEG−SMA−NO) was synthesized and integrated with oxygen-producing catalase (CAT) to fabricate a biomimetic nanoreactor (termed as CAT@PNN), aiming to enhance peroxynitrite generation upon X-ray radiation for radiosensitization. CAT@PNN effectively reduced the hypoxic levels and produced abundant NO molecules in tumors. Upon X-ray radiation, excessive peroxynitrite radicals were generated with profound spatiotemporal distribution profiles, which effectively downregulated the expression of DNA-repairing RAD51, reduced the proportion of cancer-stem like cells, and enhanced the levels of DNA damages, cell apoptosis and lipid peroxidation to aid radiosensitization. Specifically, the combination of single treatment of CAT@PNN with X-ray radiation resulted in a 95.41 % inhibition of tumor growth and significantly extended survival in 4T1 tumor model. Therefore, the biomimetic nanoreactor of CAT@PNN offers a promising peroxynitrite-generating nanoplatform to enhance radiosensitization in cancer radiotherapy.