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

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 Ca²⁺ via the lysosome pathway post-endocytosis, subsequently triggering interferon through the Ca²⁺-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.