Multifunctional miR181a nanoparticles promote highly efficient radiotherapy for rectal cancer

The development of radiotherapy technology improved outcomes in rectal cancer. Nevertheless, radiotherapy resistance has become a significant problem. This resistance is associated with tumor microenvironment (TME) hypoxia, cell cycle block, and related genetic alterations. We designed a novel miRNA-delivered and improved hypoxic microenvironment sensitization therapy for rectal cancer. With the protection of Zeolitic Imidazolate Framework-8 (ZIF-8) and the delivery of nano-manganese dioxide particles, the nanocomplex exhibited outstanding catalytic mimetic activity in decomposing hydrogen peroxide into oxygen, thus significantly reversing the TME hypoxia. The radiosensitizer miRNA-181a induces DNA damage directly after radiotherapy. We loaded miR181a into the MnO2@ZIF-8-polyethylene glycol nanocomplex to prevent its degradation in the circulatory system and successfully carry miR181a into the tumor. MiR181a-MnO2@ZIF-8 overcame radioresistance and enhanced therapeutic efficacy in a subcutaneous tumor model. This multiple sensitization strategy of the combined delivery of miR181a with MnO2@ZIF-8 nanoenzymes provides a promising therapeutic approach for rectal cancer.