Abstract：
Osteoarthritis (OA) is a progressive joint disease characterized by inflammation and cartilage destruction, and its progression is closely related to imbalances in the M1/M2 synovial macrophages. A two-pronged strategy for the regulation of intracellular/extracellular nitric oxide (NO) and hydrogen protons for reprogramming M1/M2 synovial macrophages is proposed. The combination of carbonic anhydrase IX (CA9) siRNA and NO scavenger in \"two-in-one\" nanocarriers (NAHA-CaP/siRNA nanoparticles) is developed for progressive OA therapy by scavenging NO and inhibiting CA9 expression in synovial macrophages. In vitro experiments demonstrate that these NPs can significantly scavenge intracellular NO similar to the levels as those in the normal group and downregulate the expression levels of CA9 mRNA (≈90%), thereby repolarizing the M1 macrophages into the M2 phenotype and increasing the expression levels of pro-chondrogenic TGF-β1 mRNA (≈1.3-fold), and inhibiting chondrocyte apoptosis. Furthermore, in vivo experiments show that the NPs have great anti-inflammation, cartilage protection and repair effects, thereby effectively alleviating OA progression in both monoiodoacetic acid-induced early and late OA mouse models and a surgical destabilization of medial meniscus-induced OA rat model. Therefore, the siCA9 and NO scavenger \"two-in-one\" delivery system is a potential and efficient strategy for progressive OA treatment.
摘要：
骨关节炎(OA)是一种以炎症和软骨破坏为特征的进行性关节疾病,其进展与M1/M2滑膜巨噬细胞的失衡密切相关。提出了一种调节细胞内/细胞外一氧化氮（NO）和氢质子重编程M1/M2滑膜巨噬细胞的双管齐下的策略。在“二合一”纳米载体（NAHA-CaP/siRNA纳米颗粒）中，碳酸酐酶IX（CA9）siRNA和NO清除剂的组合是通过清除NO和抑制滑膜巨噬细胞中的CA9表达而开发的，用于进行性OA治疗。体外实验表明，这些NPs可以明显清除与正常组相似的细胞内NO水平，并下调CA9mRNA的表达水平（约90％）。从而将M1巨噬细胞重新极化为M2表型，并增加软骨原TGF-β1mRNA的表达水平（约1.3倍），抑制软骨细胞凋亡。此外，体内实验表明，NPs具有很好的抗炎作用，软骨保护和修复作用，从而有效地减轻单碘乙酸诱导的早期和晚期OA小鼠模型中的OA进展以及内侧半月板诱导的OA大鼠模型的手术失稳。因此,siCA9和NO清除剂“二合一”递送系统是进行性OA治疗的潜在和有效策略。
