A major barrier in mucosal vaccine development is achieving localized immunity without systemic toxicity. Here we engineered NanoCF501, a nanoparticulate STING agonist formulated with a 2-ethyl-2-oxazoline polymer. As an adjuvant, NanoCF501 facilitates efficient mucus penetration and localized respiratory retention, minimizing systemic exposure as confirmed by pharmacokinetics in rats. In mice, intranasal co-administration of NanoCF501 (1/20th the systemic dose) with an antigen comprising multivalent fragments derived from different coronaviruses induced robust mucosal and systemic immunity, conferring protection against homologous/heterologous pan-β-coronaviruses. Single-cell transcriptomics reveals STING-dependent reprogramming of lung antigen-presenting cells, enhancing adaptive responses. Our results were further validated in non-human primates and were extended to licensed influenza vaccines, showing that NanoCF501 can be used to repurpose intramuscular antigens for mucosal delivery. By integrating nanoscale rational design with innate targeting, NanoCF501 establishes a universal adjuvant for next-generation vaccines, advancing nanomedicine for pandemic preparedness.