Zinc Ion-Coordinated Sericin Calcium Phosphate Nanovaccines Induce Hyperactive Dendritic Cells and Synergistic Activation of T Cells for Cancer Immunotherapy.

Peptide-based neoantigen vaccines are promising cancer immunotherapy strategies because of their capability to induce durable tumor-specific immune responses. However, insufficient neoantigen-specific T-lymphocyte activation greatly limits their clinical efficacy. Here, we developed sericin-coordinated zinc ion-modified calcium phosphate (CP) nanovaccines that codeliver tumor antigen peptides and a Toll-like receptor 9 agonist (SZCP/APs-CpG) for potentiating antigen-specific T cell immunity. SZCP/APs-CpG nanovaccines could yield efficient codelivery of antigen peptides and adjuvants to dendritic cells (DCs) in draining lymph nodes (dLNs), induce hyperactive DCs depending on the inflammasome-dependent interleukin-1β secretion, and coordinate the released Zn2+-induced T cell activation to elicit robust and durable antigen-specific T cell immune responses. Vaccination with SZCP/APs-CpG exhibited potent anticancer efficacy and superior safety in multiple murine cancer models and significantly protected against B16-OVA tumor rechallenge and eradicated orthotopic colon cancer in mice when combined with immune checkpoint blockade. Thus, our work presents an efficient and versatile nanovaccine platform for boosting antigen-specific T cell activation for cancer immunotherapy.