<p>Oral leukoplakia (OLK) carries a risk of malignant transformation. While adhesive hydrogels enhance drug retention in the dynamic and moist oral cavity, their inability to achieve lesion-specific adhesion or precision therapy restricts precision medicine applications. To address this, we synthesize DNA hydrogels through co-crosslinking of thiolated gelatin and thiolated oligonucleotide via disulfide bonds. During crosslinking, Mn²⁺ and chlorin e6 (Ce6) are incorporated through thiol-metal coordination and physical entrapment within the molecular network, respectively, yielding sono-activatable DNA hydrogels. To confer site-specific adhesion, low-frequency ultrasound (LFUS) is employed to anchor complementary oligonucleotide onto the lesion surface, enabling the bioadhesion of DNA hydrogels through base pairing. Under high-frequency ultrasound (HFUS), the sonosensitizer Ce6 generates substantial reactive oxygen species, triggering the mitochondrial DNA (mtDNA) release within hyperproliferative epithelial cells. Concurrent HFUS accelerates Mn²⁺ release from the hydrogel, potentiating cGAS recognition of cytosolic mtDNA and activating the cyclic GMP-AMP synthase stimulator of interferon genes (cGAS-STING) pathway. The subsequently matured dendritic cells (DCs) prime naïve T cells to differentiate into cytotoxic T lymphocytes, reversing the immunosuppressive microenvironment in OLK. Interestingly, this therapeutic modality even induces an immunological memory effect to restrain OLK recurrence and impede malignant transformation. Our study introduces the first DNA-directed hydrogel bioadhesion strategy and thus proposes unprecedented cGAS-STING pathway associated-immunotherapy against OLK.</p>