Vertex‐Integrated Tetrahedral DNA Nanoframe Enhances miR‐143‐3p Delivery for Osteoarthritis Therapy

ABSTRACT Osteoarthritis (OA) is a leading cause of global disability, characterized by chronic inflammation, progressive cartilage degradation, and subchondral bone remodeling. While microRNAs (miRNAs) like miR‐143‐3p show promising anti‐inflammatory and chondroprotective potential, their clinical application is hampered by poor stability and inefficient delivery. To address this, a vertex‐integrated tetrahedral DNA nanoframe (Tvi‐miR143) is developed for the stable and controlled delivery of miR‐143‐3p. Tvi‐miR143 system uniquely integrates miR‐143 mimics within the DNA nanostructure, maintaining native tetrahedron geometry and facilitating controlled intracellular release via RNase H‐sensitive segments and toehold‐mediated strand displacement. Tvi‐miR143 exhibits physiological stability and efficient uptake by primary chondrocytes without transfection agents. In interleukin‐1β (IL‐1β)–stimulated chondrocytes, it reduces inflammation, oxidative stress, and apoptosis, while enhancing survival and matrix synthesis, outperforming free miR‑143, bare tetrahedral DNA nanostructures (TDN), and dexamethasone, a clinically used anti‐inflammatory drug. Mechanistically, Tvi‐miR143 inhibits NF‑κB signaling, suppressing inflammatory cytokines and catabolic enzymes while upregulating cartilage matrix proteins. In an OA rat model, intra‑articular Tvi‑miR143 prolongs miRNA retention, preserves cartilage integrity, reduces matrix degradation, improves histological scores, and shows no systemic toxicity. These results highlight Tvi‑miR143 as an effective, stable, and biocompatible delivery platform that combines miR‐143 therapeutics with DNA nanotechnology, offering a promising strategy for OA therapy.