Transmucosal delivery of a dendritic cell-targeting intranasal nanovaccine boosts HIV-1 specific mucosal and systemic immune responses.

The induction of secretory IgA (sIgA) on mucosal surfaces is crucial for developing vaccines that effectively prevent Human immunodeficiency virus type 1 (HIV-1) transmission. However, the mucosal barrier significantly limits antigen absorption, resulting in weak systemic and mucosal immune responses. In this study, a novel dual-function nanovaccine for intranasal administration of HIV-1 native-like envelope (Env) proteins was developed. Specifically, the amphiphilic polymer coating (DPPD2) was synthesized by conjugating P-D2, a peptide that targets the CD11c receptor on dendritic cells (DCs), to DSPE-PEG (DP). DPPD2 was then employed to surface-functionalize the amino-modified mesoporous silica nanoparticle (MSN) that was loaded with Env and Toll-like receptor 9 agonist CpG, resulting in a DC-targeting nanovaccine. DPPD2/Env/CpG@MSN could synergistically boost trans-mucosal penetration of Env proteins and the recruitment, antigen uptake and activation of submucosal DCs. More importantly, we found that DPPD2/Env/CpG@MSN promoted germinal center (GC) responses in the muco-associated lymphoid tissue and draining lymph nodes, further leading to significantly enhanced HIV-1-specific sIgA antibody levels in situ and distant mucosal sites. Furthermore, systemic immune responses such as serum neutralizing antibodies against heterologous HIV-1 pseudoviruses and systemic T cell immunity were improved. Our study introduces a unique functional intranasal nanovaccine, providing a basis for developing subunit vaccines against mucosal viral infections. STATEMENT OF SIGNIFICANCE: The development of effective strategies to prevent mucosal transmission of HIV-1 is crucial for combating AIDS. Current HIV-1 Env subunit vaccines have shown limited immunogenicity in mucosal immunity studies. This work developed an intranasal nanovaccine, DPPD2/Env/CpG@MSN, to synergistically enhance trans-mucosal penetration of the Env protein and its subsequent uptake by submucosal DCs. The results demonstrated that DPPD2/Env/CpG@MSN effectively boosted germinal center responses and antibody production. The levels of Env-specific sIgA antibodies were significantly elevated in both local and distant mucosal sites. Moreover, the nanovaccine also elicited robust Env-specific T cell immune responses in spleen. This design provides a promising strategy for enhancing the immunogenicity of HIV-1 subunit vaccines in mucosal vaccination.