Bioorthogonal Activation of TLR7 Agonists Provokes Innate Immunity to Reinforce Aptamer-Based Checkpoint Blockade

作者：Wei Yue, Geng Qin, Zhao Wang, Chuanqi Zhao, Jinsong Ren, Xiaogang Qu · 发表于：ACS Nano · 年份：2023 · DOI：10.1021/acsnano.2c12313 · 被引用次数：58 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、Nanoplatforms for cancer theranostics

Although cancer immunotherapy based on immune checkpoint blockade has shown promising clinical responses, the limited host response rate and systemic side effects still restrict immunotherapy efficacy. To address these challenges, here, we construct an aptamer-functionalized metal–organic framework (MOF) catalyst for bioorthogonal activation of Toll-like receptors (TLR) 7 agonists and programmed death-ligand 1 (PDL1) blockade for enhanced antitumor immunotherapy. The catalyst contains ultrasmall Pd nanoparticles enabling the local activation of TLR7 agonists in native form, which results in the remodeling of the tumor microenvironment (TME). Meanwhile, the loaded PDL1 aptamers release in response to phosphate and block the PD1/PDL1 signaling pathway between T cells and cancer cells. Thus, synergy between TLR7 agonists and PDL1 blockade induces the infiltration and activation of immune cells to initiate a robust immune response, thereby simultaneously inhibiting primary and distant metastatic tumors. The immunotherapeutic effect of our design has been demonstrated in both single and bilateral subcutaneous colorectal cancer (CT26) models. In situ bioorthogonal activation of agonists may offer an alternative approach to improve the therapeutic efficacy of immunotherapy with minimized systemic toxicity. Our work will provide good inspiration for current checkpoint blockade-based immunotherapy.