Phenolic Hydroxyl-Containing Lipid Nanoparticles Enable Codelivery of HPV Peptide Antigens and Manganese Adjuvant for Cancer Immunotherapy

Therapeutic peptide vaccines against HPV-associated cancers are often limited by insufficient immunogenicity and inefficient intracellular delivery. Here, we develop a phenolic hydroxyl-containing lipid nanoparticle (EMT@LNP) as a nanomedicine platform for the coordinated codelivery of HPV16 E6/E7 peptide antigens and manganese (Mn2+) adjuvant. Distinct from conventional electrostatic loading strategies, EMT@LNP exploits hydrogen-bonding interactions between phenolic hydroxyl groups and peptide antigens, enabling charge-independent loading of peptides with diverse physicochemical properties, while coordination interactions between phenolic moieties and Mn2+ allow the simultaneous incorporation of immunostimulatory adjuvants. This dual-interaction-driven design integrates antigen delivery and innate immune activation within a single nanostructure. Functionally, EMT@LNP enhances antigen uptake and promotes dendritic cell maturation, accompanied by activation of STING-associated signaling, as indicated by increased phosphorylation of STING, TBK1, and IRF3. In vivo, EMT@LNP facilitates efficient delivery to draining lymph nodes and prolongs antigen retention following intramuscular administration. In a therapeutic TC-1 tumor model, EMT@LNP elicits potent antitumor immune responses, characterized by enhanced CD8+ T-cell infiltration and reduced immunosuppressive cell populations, leading to significant tumor growth inhibition without observable systemic toxicity. Collectively, this study presents a nanobiotechnology strategy that combines charge-independent peptide loading with metal-ion-mediated immune activation, providing a versatile and potentially translatable platform for therapeutic vaccination against HPV-associated malignancies.