Lipid nanoparticle-based mRNA platforms for mucosal HIV vaccines: formulation advances, immune mechanisms, and...

Developing an effective HIV vaccine remains a major challenge in modern medicine. The majority of HIV transmissions occur across mucosal surfaces, yet the mucosal immune protection provided by current systemic vaccination strategies is limited. However, the potential of lipid nanoparticle (LNP)-based messenger RNA (mRNA) vaccines to revolutionize HIV prevention is a source of hope and optimism. Additionally, circular RNA (circRNA) represents an emergent platform that may offer potential for mucosal HIV vaccine development. This review examines the relationship between mRNA-LNP formulation science and mucosal immunology, with a focus on how adjuvant design, device engineering, and delivery methods interact to influence protective outcomes. We summarize the most recent research on mucosal delivery methods, including nasal, vaginal, rectal, and pulmonary routes, as well as formulation techniques to overcome obstacles such as mucus penetration, enzymatic breakdown, and epithelial absorption. We also examine how mRNA design (including nucleoside modification status) and prime-boost regimens influence the desired immunological outcomes, such as the induction of mucosal secretory IgA (SIgA), tissue-resident memory T cells (T_RM), and a balanced systemic-local immune response. The microbiome and mucosal inflammation are examined in relation to safety, tolerability, and regulatory considerations. We stress the importance of future research priorities, including integrated prime-boost schedules, adjuvant tuning, and early human trials, to engage the audience and commit to the advancement of HIV prevention. We also highlight translational roadblocks, such as the lack of standardized mucosal assays, limited preclinical challenge data, and manufacturing challenges. When combined, mucosal delivery of mRNA vaccines made with LNP presents a promising strategy for preventing HIV by focusing immune responses at viral entry points.