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

作者：Guoliang Yi, Min Li, Jiayi Zhou, Jinxin Li, Xizheng Song, Siming Li, Jianghua Liu, Haowei Zhang, Zhiwei Chen · 发表于：Materials Today Bio · 年份：2025 · DOI：10.1016/j.mtbio.2025.101697 · 被引用次数：17 · 研究领域：Osteoarthritis Treatment and Mechanisms、Extracellular vesicles in disease、RNA Research and Splicing

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. Schematic depiction of the therapeutic strategy of LNPs@UA in combating OA. Study Design: In this study, we developed a novel nanomaterial using microfluidic technology, in which LNPs were used as carriers, encapsulating UA, and were modified with 2-DIP and TPP, which were termed LNPs@UA. Notably, these nanoparticles exhibit pH-responsive drug release and mitochondrial-targeting capabilities. LNPs@UA have a distinctive ability to accumulate within mitochondria. In acidic...