LAUSR

As a promising therapeutic strategy against cancer, immunotherapy faces critical challenges, especially in solid tumors. Immune checkpoint blockade therapy, particularly blocking the interaction of the programmed cell death 1 (PD1)-PD1 ligand 1 (PD-L1) axis, can reverse the suppression of T cells so as to destroy tumor cells and exert antitumor effects. Here, a strategy of multiple activation of immune pathways is developed, to provide supporting evidence for potential antitumor therapies. Briefly, a pH/glutathione responsive drug-loading hollow-manganese dioxide (H-MnO2 )-based chlorine6 (Ce6)-modified DNAzyme therapeutic nanosystem for the combination of gene therapy and immunotherapy is established. The H-MnO2 nanoparticles could efficiently deliver the DNAzyme and glycyrrhizic acid (GA) to enhance the tumor target effects. In the tumor microenvironments, the biodegradation of H-MnO2 via pH-induced hydrolyzation allows the release of guest DNAzyme payloads and host Mn2+ ions, which serve as PD-L1 mRNA-targeting reagent and require DNAzyme cofactors for activating gene therapy. In addition, Mn2+ is also associated with the immune activation of thcGAS-STING pathway. Auxiliary photosensitizers Ce6 and GA could produce reactive oxygen species, resulting in immunogenic cell death. Overall, this study provides a general strategy for targeted gene inhibition and GA release, which is valuable for the development of potential tumor immunotherapies.