Abstract

Growing evidences have proved that RNA-editing enzyme ADAR1, responsible for detecting endogenous RNA species, is significantly associated with poor response or resistance to immune checkpoint blockade (ICB) therapy. Here, a genetically engineered nanovesicle (siAdar1-LNP@mPD1) was developed as an RNA interference (RNAi) nano-tool to overcome tumor resistance to ICB therapies. Small interfering RNA against ADAR1 (siAdar1) was packaged into a lipid nanoparticle (LNP), which was further coated with plasma membrane extracted from the genetically engineered cells overexpressing PD1. siAdar1-LNP@mPD1 could block the PD1/PDL1 immune inhibitory axis by presenting the PD1 protein on the coating membranes. Furthermore, siAdar1 could be effectively delivered into cancer cells by the designed nanovesicle to silence ADAR1 expression, resulting in an increased type I/II interferon (IFN-β/γ) production and making the cancer cells more sensitive to secreted effector cytokines such as IFN-γ with significant cell growth arrest. These integrated functions confer siAdar1-LNP@mPD1 with robust and comprehensive anti-tumor immunity, as evidenced by significant tumor growth regression, abscopal tumor prevention, and effective suppression of lung metastasis, through a global remodeling of the tumor immune microenvironment. Overall, we provided a promising translatable strategy to simultaneously silence ADAR1 and block PDL1 immune checkpoint to boost robust antitumor immunity.