Engineering a Lipid Nanoparticle with Atypical Calcium Crystal Structure for Enhanced IFNβ‐Mediated Immunotherapy

Abstract Immune checkpoint inhibitors have revolutionized cancer therapy; however, many patients exhibit suboptimal responses, which is due to inadequate T cell priming by the innate immune response. Metal ions play a critical role in modulating the innate immune response. However, the mechanisms by which metal ions facilitate dendritic cell maturation through the activation of interferon remain poorly understood. This research identifies a nanomaterial Calcium phosphate‐containing liposome (NanoCa), characterized by an atypical crystal structure and pH‐responsive profile. NanoCa promotes bone marrow‐derived dendritic cell maturation and exhibits antiviral effects and anti‐tumor properties in different tumor models. Also, NanoCa acts as an immunostimulant by fostering antibody production. Furthermore, when combined with programmed cell death 1 receptor (PD‐1) blocking antibodies, NanoCa synergistically enhances anti‐tumor efficacy in CT26 models. Mechanistically, NanoCa rapidly releases Ca 2+ via the lysosome pathway post‐endocytosis, subsequently triggering interferon through the Ca 2+ ‐calcineurin (CaN) ‐ nuclear factor of activated T cells 2 (NFATc2) ‐ protein kinase C beta (PKCβ) ‐ interferon regulatory factor 3 (IRF3) signal pathway. Single‐cell RNA sequencing (scRNA‐seq) shows NanoCa increases the population of tumoral infiltrating dendritic cell (DC), C1qc+ TAM, and CD8T_eff cells and decreases the CD8T_ex and immunosuppressive SPP1+ TAM population in tumor‐draining lymph nodes. Overall, NanoCa shows translational potential for anti‐tumor immune therapeutics.