The oral mucosa is a potent yet challenging site for vaccination, where physiological barriers and a tolerogenic immune microenvironment often limit effective immune response. However, existing delivery systems struggle to overcome these obstacles. Herein, we developed an oral mucosal nano-vaccine (MnZ-NV) via Mn²⁺-zoledronate coordination to co-encapsulate the Toll-like receptor 4 (TLR4) agonist Kdo2-lipid A (KLA) and antigen ovalbumin (OVA) within sub-50 nm particles. Upon sublingual administration, MnZ-NV demonstrated augmented mucosal penetration, lymph node targeting and dendritic cell activation, stimulating robust local and systemic cellular/humoral immunity. Furthermore, it induced trained immunity through splenic monocyte activation and bone marrow progenitor reprogramming, eliciting significant therapeutic and prophylactic efficacy against in-situ oral carcinoma, lung-metastatic melanoma, and pathogenic oral dysbiosis. This work provides a promising strategy that synergistically integrates innate, adaptive, and trained immunity for advanced mucosal immunotherapy.