Itaconate-functionalized tetrahedral framework nucleic acids break the dry eye vicious cycle through dual antioxidant and anti-inflammatory actions.

Dry eye disease (DED) is a prevalent ocular surface disorder characterized by chronic inflammation and oxidative stress, significantly impacting vision and quality of life. Although reactive oxygen species (ROS) serve as a key upstream regulator that initiate and perpetuate inflammatory cascades in DED, current clinical therapies predominantly target downstream inflammatory pathways, leading to suboptimal treatment outcomes. To address this limitation, we developed a novel mucin-1 (MUC1)-targeted nanotherapeutic platform (tFNA-IM) by integrating the dual antioxidant and anti-inflammatory agent itaconate (ITA) with ROS-scavenging tetrahedral framework nucleic acids (tFNA) for efficient DED treatment. The engineered tFNA-IM exhibits uniform nanostructure and optimal size distribution, enabling deep penetration into ocular tissues, while the conjugated MUC1 aptamer significantly enhances cellular internalization in human corneal epithelial cells (HCECs), as demonstrated by confocal microscopy and flow cytometry analyses. Functionally, tFNA-IM effectively neutralizes ROS, reduces apoptosis, and downregulates pro-inflammatory cytokines in vitro, demonstrating potent anti-oxidative and anti-inflammatory capabilities. In a murine DED model, tFNA-IM exhibits prolonged ocular retention and superior therapeutic efficacy, markedly improving corneal epithelial integrity and suppressing inflammatory responses. These findings establish aptamer-functionalized tFNA as a precision nanoplatform for ocular drug delivery, offering a synergistic therapeutic strategy to disrupt the ROS-inflammatory vicious cycle in DED. GRAPHICAL ABSTRACT: [Figure: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12951-025-03742-y.