Novel pH-responsive lipid nanoparticles deliver UA-mediated mitophagy and ferroptosis for osteoarthritis treatment.

Synovial inflammation plays a crucial role in osteoarthritis (OA) development, leading to chronic inflammation and cartilage destruction. Although targeting synovitis can alleviate OA, clinical outcomes have been disappointing due to poor drug targeting and joint cavity heterogeneity. This study presents pH-responsive lipid nanoparticles (LNPs@UA), loaded with Urolithin A (UA), as a potential OA treatment. LNPs@UA showed uniform particle size, low zeta potential, and effective mitochondria-targeting and pH-responsive capabilities. In vitro, LNPs@UA reduced reactive oxygen species (ROS), pro-inflammatory factors (IL-1β, IL-6, TNF-α), and promoted M2 macrophage polarization. It improved mitochondrial structure, enhanced autophagy, and inhibited ferroptosis. In vivo, LNPs@UA alleviated OA progression in an ACLT-induced OA mouse model. Transcriptomic analysis revealed inhibition of NF-κB signaling and activation of repair pathways. These results suggest LNPs@UA could offer a promising therapeutic approach for OA.