Platinum(IV)-Backboned Polymer Prodrug-Functionalized Manganese Oxide Nanoparticles for Enhanced Lung Cancer Chemoimmunotherapy via Amplifying Stimulator of Interferon Genes Activation

Abstract

The stimulator of interferon genes (STING) pathway exhibits great potential in remodeling the immunosuppressive tumor microenvironment and initiating antitumor immunity. However, how to effectively activate STING and avoid undesired toxicity after systemic administration remains challenging. Herein, platinum(IV)-backboned polymer prodrug-coated manganese oxide nanoparticles (DHP/MnO₂NP) with pH/redox dual responsive properties are developed to precisely release cisplatin and Mn²⁺ in the tumor microenvironment and synergistically amplify STING activation. In vitro, we demonstrate that DHP/MnO₂NP can effectively induce tumor cell DNA damage and leak into the cytoplasm, cooperating with Mn²⁺ to promote STING activation and significantly upregulate the expression of proinflammatory cytokines. Additionally, DHP/MnO₂NP can selectively release cisplatin and Mn²⁺ to mediate tumor killing while reducing toxicity to normal cells. In vivo, DHP/MnO₂NP exerted increased therapeutic efficacy by inducing STING activation and initiating robust antitumor immunity. Specifically, DHP/MnO₂NP effectively skewed tumor-associated macrophages toward a proinflammatory phenotype and upregulated the expression of proinflammatory cytokines in tumors by up to 99-fold relative to the control. And the infiltration of CD8⁺ T cells was also significantly increased. When STING signaling was blocked, the antitumor effects and immunostimulatory efficacy of DHP/MnO₂NP were significantly inhibited. Moreover, DHP/MnO₂NP possess the advantage of enhanced tumor homing and retention, resulting in stronger and longer-lasting anticancer effects. Overall, DHP/MnO₂NP provide a potential platform for potentiating cancer chemoimmunotherapy and hold promise for precision treatment.