WYRGRL-functionalized tetrahedral DNA integrates ROS scavenging and miR-26b-5p delivery for cartilage-specific osteoarthritis treatment

MicroRNAs (miRNAs) are key regulators of diverse physiological and pathological processes, including osteoarthritis (OA), a degenerative joint disease characterized by progressive cartilage loss. Among them, miR-26b-5p mitigates inflammation, inhibits chondrocyte hypertrophy, and delays cellular senescence, but its therapeutic application is limited by poor stability, inefficient delivery, and low cellular uptake. Tetrahedral framework nucleic acids (tFNAs), a class of self-assembled three-dimensional DNA nanostructures, offer excellent biocompatibility, structural stability, and high transmembrane transport efficiency, making them promising miRNA carriers. In this study, we developed a cartilage-targeting nanoplatform (WT@miR) by conjugating tFNAs with the WYRGRL peptide, which binds specifically to collagen IIα1, and loading them with miR-26b-5p. In chondrocytes subjected to tert-butyl hydroperoxide (TBHP)–induced oxidative stress, WT@miR provided dual protection by scavenging reactive oxygen species (ROS) and releasing therapeutic miR-26b-5p, thereby suppressing inflammatory cascades, oxidative injury, and senescence. In a mouse anterior cruciate ligament transection (ACLT) model, WT@miR significantly attenuated cartilage degeneration and delayed OA progression. Mechanistically, miR-26b-5p directly targeted THRAP3, activating SOX9 and AMPK signaling pathways. These findings highlight WT@miR as a potent disease-modifying therapy for OA and establish a versatile nucleic acid delivery platform with broad translational potential. We engineered a cartilage-targeted nanoplatform (WT@miR) by functionalizing tetrahedral DNA nanostructures with WYRGRL and loading miR-26b-5p. WT@miR combines intrinsic ROS scavenging and THRAP3 silencing, thereby restoring AMPK and SOX9 signaling to protect cartilage and inhibit subchondral bone sclerosis in osteoarthritis. • WT@miR was built from WYRGRL-modified tetrahedral DNA nanostructures. • The system enables precise and efficient delivery of miR-26b-5p to cartilage. • WT@miR shows dual therapeutic effects: ROS scavenging and gene silencing. • THRAP3 inhibition restores SOX9 and AMPK signaling, protecting cartilage. • WT@miR attenuates OA progression and subchondral bone sclerosis in vivo.