Key Takeaways & Executive Findings
- •• • The hydrogel achieves lesion-specific adhesion via DNA base pairing, with LFUS anchoring complementary oligonucleotides; this precision targeting minimizes collateral damage to healthy tissue, a critical improvement over generic adhesive hydrogels. • • Under HFUS, Ce6 generates substantial reactive oxygen species, triggering mtDNA release; concurrent HFUS accelerates Mn2+ release, potentiating cGAS-STING activation. This dual-action mechanism enhances immunotherapy efficacy, as evidenced by dendritic cell maturation and cytotoxic T lymphocyte priming. • • The cGAS-STING pathway activation is Mn2+-dependent, with Mn2+ enhancing sensitivity to dsDNA (as per reference 67). This synergy between sonodynamic therapy and STING agonism offers a potent approach to reverse immunosuppression in OLK. • • The therapy induces immunological memory, which is crucial for preventing OLK recurrence and malignant transformation, addressing a key clinical unmet need in premalignant lesion management.
Abstract
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.
1. Introduction
Oral leukoplakia (OLK) is a chronic lesion with malignant potential, yet current treatments suffer from poor retention in the dynamic oral cavity. Existing adhesive hydrogels rely on generic hydrogen bonding, lacking tissue-specific adhesion, which leads to off-target effects and suboptimal precision. This bottleneck restricts the clinical translation of local therapies for OLK.
Our approach introduces DNA-directed bioadhesion, using complementary oligonucleotide anchoring via low-frequency ultrasound to achieve lesion-specific hydrogel adhesion. This precision targeting, combined with sono-activatable release of Mn2+ and Ce6, activates the cGAS-STING pathway, offering a novel immunotherapeutic strategy that not only treats OLK but also induces immunological memory to prevent recurrence.
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Yiming Kong, Yao Xu, Dantong Zheng, Hao Wang, Yishan Li, Qirong Tang, Yong Hu (2026). DNA-Directed Adhesion of a Sono-Activatable Hydrogel to Oral Leukoplakia Lesion for cGAS-STING Pathway Associated-Immunotherapy. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-026-4134-6
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Frequently Asked Questions
What is the mechanism for lesion-specific adhesion, and how does it compare to conventional adhesive hydrogels?
The hydrogel uses DNA base pairing: low-frequency ultrasound anchors complementary oligonucleotides onto the lesion surface, enabling specific bioadhesion. This contrasts with conventional hydrogels that rely on non-specific hydrogen bonding, which cannot achieve tissue selectivity. The DNA-directed approach ensures precise targeting, reducing collateral damage to healthy mucosa.
How does the hydrogel achieve controlled release of Mn2+ and Ce6 under ultrasound?
Mn2+ is incorporated via thiol-metal coordination, and Ce6 via physical entrapment. High-frequency ultrasound (HFUS) triggers the release: it accelerates Mn2+ release and activates Ce6 to generate reactive oxygen species. This dual release is spatially and temporally controlled by ultrasound application, enabling on-demand therapy.
What evidence supports the activation of the cGAS-STING pathway and its therapeutic impact?
The study demonstrates that HFUS-induced mtDNA release, combined with Mn2+ (which enhances cGAS sensitivity to dsDNA), activates STING. This leads to dendritic cell maturation and cytotoxic T lymphocyte priming, reversing the immunosuppressive microenvironment. The induction of immunological memory further prevents recurrence, as shown in the abstract.
What are the potential scalability and translational challenges for this hydrogel system?
Scalability depends on the synthesis of thiolated gelatin and oligonucleotides, which are well-established. However, the need for low-frequency ultrasound to anchor DNA and high-frequency ultrasound for therapy requires specialized equipment, which may limit widespread clinical adoption. Cost and regulatory approval for the DNA components and ultrasound protocols are additional hurdles.
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