Antigen self-presenting dendrosomes swallowing nanovaccines boost antigens and STING agonists codelivery for cancer immunotherapy

Abstract

Cancer vaccines show promise by eliciting tumor-specific cytotoxic T lymphocytes (CTL) responses. Efficient cytosolic co-delivery of antigens and adjuvants to dendritic cells (DCs) is crucial for vaccines to induce anti-tumor immunity. However, peptide- or nucleic acid-based biomolecules like tumor antigens and STING agonist cyclic-di-GMP (cdGMP) are prone to endosomal degradation, resulting in low cytosolic delivery and CTL response rates. Cationic nanocarriers can improve cytosolic delivery, but their positive charges induce off-target effects. Here, we develop cationic poly(ester amide) based nanoparticles co-loaded with antigens and adjuvant cdGMP (NP(cG, OVA)) for efficient cytosolic delivery and swallow them within antigen self-presenting DCs-derived dendrosomes (ODs) for lymph nodes (LNs) homing. The constructed dendrosomes swallowing nanovaccines ODs/NP(cG, OVA) demonstrated significantly reduced liver accumulation and enhanced LNs and DCs targeting compared to NP(cG, OVA). ODs/NP(cG, OVA) effectively cross-dressed the antigen epitopes on the shell to DCs and facilitated internalization of NP(cG, OVA), realizing DCs cytosolic co-delivery of antigens and adjuvants, thereby promoting antigen presentation, maturation and inflammatory cytokines secretion of DCs. Consequently, DCs stimulated by ODs/NP(cG, OVA) effectively induced activation, proliferation, and differentiation of antigen-specific CTLs that provided robust immune protection against tumor invasion. This work presents a powerful vaccine strategy for cancer immunotherapy.