DNA-Directed Adhesion of a Sono-Activatable Hydrogel to Oral Leukoplakia Lesion for cGAS-STING Pathway Associated-Immunotherapy
Oral leukoplakia (OLK) is a prevalent premalignant lesion with malignant transformation risk. Current adhesive hydrogels lack lesion-specific adhesion and precision therapy. We synthesized DNA hydrogels via co-crosslinking of thiolated gelatin and thiolated oligonucleotide through disulfide bonds, incorporating Mn2+ and chlorin e6 (Ce6) via thiol-metal coordination and physical entrapment. Low-frequency ultrasound (LFUS) anchored complementary oligonucleotides onto the lesion surface, enabling site-specific bioadhesion through base pairing. Under high-frequency ultrasound (HFUS), Ce6 generated reactive oxygen species, triggering mitochondrial DNA (mtDNA) release in hyperproliferative epithelial cells. Concurrent HFUS accelerated Mn2+ release, potentiating cGAS recognition of cytosolic mtDNA and activating the cGAS-STING pathway. This induced dendritic cell maturation, priming naïve T cells into cytotoxic T lymphocytes, reversing the immunosuppressive microenvironment. The modality induced immunological memory, restraining OLK recurrence and impeding malignant transformation. This study introduces the first DNA-directed hydrogel bioadhesion strategy and proposes unprecedented cGAS-STING pathway-associated immunotherapy against OLK.