Biomimetic PRMT1 inhibitor-loaded manganese-containing bimetallic MOF enhances NSCLC immunotherapy via cGAS-STING...

Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide, and its response to immune checkpoint blockade is frequently limited by an immunosuppressive tumor microenvironment and insufficient innate immune activation. Here, we developed a biomimetic manganese-containing bimetallic metal-organic framework (MOF) nanosystem, termed PMOFM, for enhanced NSCLC immunotherapy through PRMT1 inhibition, cGAS-STING activation, and PD-L1 blockade. PMOFM was constructed by loading a PRMT1-selective inhibitor into a manganese-containing bimetallic MOF and coating the nanoparticle with an anti-PD-L1-conjugated macrophage membrane to confer tumor-targeting and immunoregulatory properties. PMOFM exhibited favorable physicochemical characteristics, colloidal stability, efficient drug loading, and enhanced tumor accumulation. Mechanistically, PMOFM relieved PRMT1-mediated suppression of cGAS, while Mn²⁺ release further enhanced cGAMP-STING signaling, resulting in increased cGAMP production, elevated cGAS and pSTING expression, and amplified downstream inflammatory responses. In both subcutaneous and orthotopic NSCLC mouse models, PMOFM achieved superior tumor suppression and significantly prolonged survival without evident systemic toxicity. Moreover, PMOFM markedly increased intratumoral IFN-β, CXCL10, TNF-α, IL-6, and IFN-γ levels and promoted CD4⁺ and CD8⁺ T-cell infiltration. Collectively, this study presents a biomimetic MOF-based nanoplatform that integrates innate immune priming with immune checkpoint blockade, providing a promising strategy for enhancing immunotherapy against NSCLC.