Engineered tumor cell membrane-coated manganese-amplified STING nanoagonist potentiates PD-L1 blockade immunotherapy in non-small cell lung cancer.

Abstract

Immune checkpoint blockade targeting the PD-1/PD-L1 axis has improved the treatment of non-small cell lung cancer (NSCLC), yet its therapeutic efficacy remains limited by insufficient antitumor immune activation. Herein, we developed a biomimetic manganese-amplified STING nanoagonist to potentiate PD-L1 blockade immunotherapy. Hollow mesoporous manganese silicate nanoparticles were engineered as Mn2⁺-releasing nanocarriers for loading a STING agonist (Sa) diABZI, followed by coating with anti-PD-L1 antibody-functionalized NSCLC tumor cell membranes. The resulting Sa@HMMSN@PM exhibited pH-responsive Sa release, preserved PD-L1 blocking activity, and enhanced tumor-cell-selective uptake. Mechanistically, Mn2⁺ released from HMMSN promoted cGAMP production, while Sa further enhanced STING phosphorylation, leading to robust STING activation. Sa@HMMSN@PM showed enhanced tumor accumulation, superior tumor growth inhibition and prolonged survival in both subcutaneous and orthotopic NSCLC mouse models. Further mechanistic studies demonstrated increased IFN-β, CXCL10, TNF-α, IL-6, and IFN-γ levels, together with enhanced CD4⁺ and CD8⁺ T-cell infiltration. Importantly, Sa@HMMSN@PM exhibited favorable biosafety without obvious systemic toxicity. Overall, this biomimetic Mn2⁺-amplified STING nanoagonist provides a promising strategy for integrating innate immune activation with immune checkpoint blockade for enhanced NSCLC immunotherapy.