Reprogramming Macrophage Polarization, Depleting ROS by Astaxanthin and Thioketal‐Containing Polymers Delivering Rapamycin for Osteoarthritis Treatment

• Published in: Advanced science Vol. 11; no. 9; pp. e2305363 - n/a
• Main Authors: Li, Huiyun, Yuan, Yusong, Zhang, Lingpu, Xu, Chun, Xu, Hailin, Chen, Zhiwei
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.03.2024; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Arthritis; Astaxanthin; Autophagy; Bioavailability; Cartilage; Cytokines; Genotype & phenotype; Hemodialysis; Inflammation; macrophage polarization; Macrophages; Mice; Nanomaterials; Nanoparticles; Nitric oxide; Nonsteroidal anti-inflammatory drugs; Osteoarthritis; Osteoarthritis - drug therapy; Polymers; rapamycin; Reactive Oxygen Species - therapeutic use; thioketal; Tumor necrosis factor-TNF; Xanthophylls - pharmacology; Xanthophylls - therapeutic use; macrophage polarization; thioketal; Astaxanthin; osteoarthritis; rapamycin
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202305363

Osteoarthritis (OA) is a chronic joint disease characterized by synovitis and joint cartilage destruction. The severity of OA is highly associated with the imbalance between M1 and M2 synovial macrophages. In this study, a novel strategy is designed to modulate macrophage polarization by reducing intracellular reactive oxygen species (ROS) levels and regulating mitochondrial function. A ROS‐responsive polymer is synthesized to self‐assemble with astaxanthin and autophagy activator rapamycin to form nanoparticles (NP@PolyRHAPM). In vitro experiments show that NP@PolyRHAPM significantly reduced intracellular ROS levels. Furthermore, NP@PolyRHAPM restored mitochondrial membrane potential, increased glutathione (GSH) levels, and promoted intracellular autophagy, hence successfully repolarizing M1 macrophages into the M2 phenotype. This repolarization enhanced chondrocyte proliferation and vitality while inhibiting apoptosis. In vivo experiments utilizing an anterior cruciate ligament transection (ACLT)‐induced OA mouse model revealed the anti‐inflammatory and cartilage‐protective effects of NP@PolyRHAPM, effectively mitigating OA progression. Consequently, the findings suggest that intra‐articular delivery of ROS‐responsive nanocarrier systems holds significant promise as a potential and effective therapeutic strategy for OA treatment. A novel reactive oxygen species‐responsive biodegradable nanoparticle (NP@PolyRHAPM) is designed, in which astaxanthin can reduce intracellular ROS levels and rapamycin‐enhanced autophagy levels, and restore mitochondrial function, hence successfully repolarizing M1 macrophages into M2 phenotypes. This repolarization enhances the proliferation and viability of chondrocytes while inhibiting apoptosis. Overall, this ROS‐responsive nanocarrier system provides a new avenue for progressive OA therapy.