Nanoenabled Disruption of Multiple Barriers in Antigen Cross-Presentation of Dendritic Cells via Calcium Interference for Enhanced Chemo-Immunotherapy

Chemo-immunotherapy holds the advantage of specific antitumor effects by activating T cell immune response. However, the efficiency of chemo-immunotherapy is restricted to the insufficient antigen presentation of dendritic cells (DCs) in the tumor immunosuppression microenvironment. Here, we rationally designed a simple yet versatile calcium ion nanogenerator to disrupt the autophagy inhibition condition within DCs, enrich damage-associated molecular patterns (DAMPs), and attenuate acidity in the tumor microenvironment. After chemotherapy, honeycomb calcium carbonate (CaCO₃) nanoparticles (OVA@CaCO₃, denoted as HOCN, ovalbumin (OVA) acted as skeleton) could preferentially accumulate in the tumor and display a series of benefits for disrupting multiple barriers in antigen cross-presentation of DCs: (i) recovering cell viability of DCs by HOCN-induced tumor acidity attenuating; (ii) disrupting the autophagy inhibition condition in DCs by generating Ca²⁺ in cells; (iii) improving maturation of DCs by Ca²⁺ overloading-mediated enhanced DAMP release from tumor cells. In addition, HOCN can also disrupt the immunosuppressive microenvironment by reducing the infiltration of immunosuppressive cells and factors. We believe regulation of the intratumoral Ca²⁺ offers an alternative strategy for improving cancer chemo-immunotherapy.