Cartilage-targeted siMMP13 delivery using cap-modified tetrahedral framework nucleic acids for Osteoarthritis therapy.

Abstract

Osteoarthritis (OA) is a degenerative joint disorder characterized by cartilage deterioration, with limited therapeutic options available to halt disease progression. A key driver of this pathology is the chondrocyte overexpression of matrix metalloproteinase 13 (MMP13), an enzyme that degrades type II collagen (Col2). Although small interfering RNA (siRNA) mediated silencing of MMP13 has shown therapeutic potential, its clinical translation is hindered by poor stability, inadequate cartilage infiltration, and a short joint residence time. To overcome these barriers, we engineered a cartilage-specific delivery system, Cap-tFNA-siMMP13 (Cats), by conjugating tetrahedral framework nucleic acid (tFNA) with cartilage-affinity peptides (Cap) to achieve efficient transport of siMMP13. The tFNA is an innovative DNA-based nanocarrier with excellent stability and cellular uptake capability. Beyond serving as delivery vehicles, tFNA also demonstrates intrinsic bioactivities including anti-inflammatory, antioxidant, and pro-proliferative effects on chondrocytes, making it particularly suitable for OA therapy. The resulting Cats nanoplatform demonstrated precise chondrocyte targeting, robust cellular uptake, and prolonged intra-articular retention. This led to potent downregulation of MMP13, which in turn mitigated inflammation and oxidative stress, inhibited chondrocyte apoptosis, and promoted cartilage matrix synthesis. In a rat model of OA, intra-articular injection of Cats effectively preserved the morphological integrity of both cartilage and subchondral bone. Our findings establish the Cats platform as a promising, multi-faceted therapeutic strategy for effective OA treatment.