Adjuvant-metal-ion-chelating PTEN mRNA with cell-membrane-coating augments the immune sensitivity for precise cancer immunotherapy

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) messenger RNA (mRNA) delivery has fueled a great hope for tumor immunotherapy via augmenting the immune sensitivity in many human cancers. However, therapeutic efficacy and clinical translation are limited by inadequate mRNA expression, insufficient immune stimulation and stringent storage requirements. Herein, inspired by the intrinsic properties of metal ions and exosomes, we developed a biomimetic delivery system (Mn-NP@PM) with superior stability for precise colorectal cancer immunotherapy. This platform employs adjuvant-metal-ion chelation for PTEN mRNA loading and PD-L1 antibodies (αPD-L1)-modified monocyte-macrophage membrane coating for mRNA protection and tumor targeting. Mn2+ was specifically selected due to its capacity for reversible mRNA binding through weak non-electrostatic interactions, facilitating efficient release, while simultaneously activating the stimulator of interferon genes (STING) pathway. Importantly, Mn-NP@PM exhibited membrane fusion for immediate cytosolic mRNA delivery, bypassing endo-lysosomal escape, optimizing transportation efficiency. Clinical-data-driven analyses further demonstrated that Mn-NP@PM-mediated PTEN restoration significantly increased T-cell infiltration and strengthened antitumor immunity in humanized patient derived xenograft (PDX) models. Collectively, this biomimetic, metal-ion-chelating, membrane-coated mRNA delivery system represents a versatile and clinically translatable strategy for personalized cancer immunotherapy.