Nanoengineered STING Mucosal Adjuvant Activates Coordinated Mucosal-Systemic Immunity for Durable Cross-Protective Defense

A longstanding barrier in vaccinology has been the inability to reconcile potent mucosal immune activation with systemic tolerability, hindering adjuvant development for over a century. Here, we present NanoCF501, a nanoparticulate STING agonist engineered with respiratory-tuned, clinically safe polymers, which overcomes this fundamental limitation. When co-administered with a multivalent pan-β-coronavirus subunit vaccine, NanoCF501 at 1/20th the systemic adjuvant dose elicits coordinated mucosal-systemic immunity, inducing robust and durable cross-protective responses. These include mucosal secretory IgA and tissue-resident memory T cells alongside systemic neutralizing antibodies, memory B cells, and long-lived plasma cells persisting >12 months in murine models. Non-human primates validate the dual-axis mucosal-systemic coupling, while toxicology studies in rats demonstrate more than 18-fold safety margin and undetectable systemic exposure, underscoring translational viability. Mechanistic interrogation via single-cell transcriptomics reveals that NanoCF501 drives STING-dependent innate immune activation, orchestrating broad transcriptional reprogramming in lung antigen-presenting cells and efficient priming of adaptive T and B cell responses. Notably, NanoCF501 converts conventional quadrivalent influenza subunit vaccines into mucosal immunogenic formulations, demonstrating platform versatility. By integrating rational nanocarrier design with innate immune targeting, this work establishes a universal mucosal vaccination strategy with broad implications for pandemic preparedness and mucosal vaccinology.