Abstract

Periodontitis is a chronic inflammatory disease driven by oral microbial dysbiosis and dysregulated host immunity, in which Porphyromonas gingivalis (Pg) and its lysine-specific gingipain (Kgp) are key pathogenic factors. Although immune targeting of Kgp holds promise for interrupting disease progression, inefficient transmucosal antigen delivery and limited dendritic cell (DC) activation hinder effective mucosal and humoral immune responses. Here, we report a sublingual mucosal nanovaccine based on tetrahedral framework nucleic acids (tFNAs) for precise DC-directed immunomodulation. The vaccine integrates a DC-targeting aptamer, a Kgp-specific antigenic peptide (KAS1), and Cytosine–phosphate–guanine oligodeoxynucleotide (CpG ODNs) adjuvant within a programmable tFNAs scaffold and is embedded in a biodegradable mixed polyethylene glycol–based (MixPEG) hydrogel to enable spatially controlled assembly and sustained sublingual delivery. Leveraging the intrinsic transmucosal transport capability of tFNAs and the bioadhesive properties of the hydrogel, this system achieves noninvasive sublingual administration and efficient uptake by local DCs, inducing notable Kgp-specific immune responses. In a murine periodontitis model, sublingual immunization enhances salivary IgA production, suppresses Pg colonization, attenuates periodontal inflammation, and mitigates alveolar bone loss, representing a potentially promising strategy for periodontitis.