STING-activating dendritic cell-targeted nanovaccines that evoke potent antigen cross-presentation for cancer immunotherapy
Nanovaccine-based immunotherapy has recently attracted significant attention for its potential to regulate immune responses and establish long-lasting protective immunity. Despite this progress, effectively presenting tumor peptide-major histocompatibility complexes to T lymphocytes remains a challenge in achieving robust antitumor immunity. A particularly promising target is the type 1 conventional dendritic cell (cDC1) subset, given its crucial role in cross-presenting exogenous antigens to CD8+ T cells. In this context, we introduce a DC-derived nanovaccine, termed Si9GM, designed to selectively target cDC1s while minimizing premature antigen release to facilitate effective stimulator of interferon genes (STING)-mediated antigen cross-presentation. This system employs bone marrow dendritic cell (BMDC)-derived membranes linked with a cDC1-specific antibody (αCLEC9A) and bound to a tumor peptide (OVA257-264), which are then coated onto dendrimer-like polyethylenimine (PEI)-grafted silica 2′,3′-cGAMP nanoparticles. The nanovaccine’s hierarchical center-radial pores are engineered to carry different molecular weight cargos, including αCLEC9A-OVA257-264 conjugates and 2’3′-cGAMP STING agonists, enabling lysosome escape for potent antigen cross-presentation and subsequent type I interferon activation. Notably, Si9GM vaccination promotes the upregulation of cytotoxic T cells, reduces tumor regulatory T cells (Tregs), induces M1/M2 macrophage polarization, and generates an immune response that works synergistically with αPD-1 immune checkpoint blockade. This nanovaccine demonstrates a dual capability to act as both an artificial antigen-presenting cell for direct T cell activation and to facilitate DC subset maturation, highlighting its potential application in clinical therapy and precision medicine.