A biomimetic pH-responsive manganese carbonate nanoparticle efficiently delivers STING agonist for high-risk neuroblastoma immunotherapy

Cyclic dinucleotides are promising STING agonists for cancer immunotherapy, yet their clinical translation is hampered by poor cellular uptake, rapid clearance, and inefficient cytosolic delivery. Here, we report a cancer cell membrane-biomimetic nanoplatform (MV@CMNPs) that enables high-efficiency encapsulation of 2′,3′-cyclic GMP-AMP (2′,3′-cGAMP) and tumor-microenvironment-responsive release, amplifying the cGAS/STING axis for robust antitumor immunity. MV@CMNPs comprise biodegradable manganese carbonate (MnCO 3 ) nanoparticles loaded with 2′,3′-cGAMP and cloaked with high-risk neuroblastoma cell membranes. The MnCO 3 core affords high drug encapsulation and pH-responsive release, while degradation-released Mn2 + may add immunomodulatory activity. The membrane coating enhances physiological colloidal stability, mediates homologous tumor targeting, and promotes membrane-facilitated endocytosis for efficient intracellular agonist delivery. MV@CMNPs augment 2′,3′-cGAMP bioactivity and amplify STING signaling in both the tumor microenvironment (TME) and tumor-draining lymph nodes (TDLNs). This dual-site activation synergistically induces type I interferon and inflammatory cytokine secretion, driving dendritic cell maturation and T cell responses to reprogram immunosuppressive tumors into immunogenic niches. In preclinical neuroblastoma models, MV@CMNPs significantly suppressed tumor growth and prolonged survival via both intratumoral and intravenous administration. This study validates biomimetic nanoparticles as a strategy to amplify STING-mediated innate immunity for cancer immunotherapy.