Intranasal fluorinated nano-adjuvant orchestrates CCL2-driven pre-DC recruitment and transmucosal antigen delivery to elicit long-term immunity against influenza.

Intranasal vaccines offer the unique advantage of inducing mucosal immunity to prevent influenza infection at the portal of entry. However, its efficacy is compromised by two major barriers, limited reservoir of resident conventional dendritic cells (cDCs) for antigen presentation and poor transmucosal delivery of antigen. Herein, we engineered a versatile intranasal vaccine nano-adjuvant, mannose-modified fluorinated PEI (MFPEI), to synergistically overcome these challenges. MFPEI combined fluoroalkane-mediated mucus penetration, mannose-assisted DCs targeting, and TLR4/NF-κB pathway activation. The fluorinated backbone endowed MFPEI/HA with hydrophobic and lipophobic characteristics, minimizing mucin entrapment and significantly enhancing antigen penetration across the mucosal layer. Concurrently, MFPEI activated TLR4/NF-κB signaling pathway in DCs, promoting CCL2 secretion and subsequently facilitating precursor dendritic cells (pre-DCs) recruitment via CCR2-CCL2 pathway to replenish the nasal cDCs network. This dual strategy maximized antigen uptake and presentation, culminating in potent and durable mucosal and systemic immunity that conferred complete immune protection against influenza infection. Our study establishes MFPEI as a promising nano-adjuvant platform for next-generation intranasal vaccines against influenza and other respiratory pathogens.