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  3. Synergistic rheumatoid arthritis therapy by interrupting the detrimental feedback loop to orchestrate hypoxia M1 macrophage polarization using an enzyme-catalyzed nanoplatform

Synergistic rheumatoid arthritis therapy by interrupting the detrimental feedback loop to orchestrate hypoxia M1 macrophage polarization using an enzyme-catalyzed nanoplatform

  • Bioact Mater. 2024 Jul 23:41:221-238. doi: 10.1016/j.bioactmat.2024.07.026.
Dong Guo 1 2,  Hui Liu 1 2 3,  Sheng Zhao 3,  Xinya Lu 1 2,  Haoyu Wan 1 2,  Yitao Zhao 1 2,  Xinzhi Liang 1 2,  Anbiao Zhang 1 2,  Mengyuan Wu 3,  Zhisheng Xiao 1 2,  Ning Hu 4,  Zhong Li 5,  Denghui Xie 1 2
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, PR China.
  • 2 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, 510630, PR China.
  • 3 Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, School of Materials and Energy, Southwest University, Chongqing, 400715, PR China.
  • 4 Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China.
  • 5 Department of Biomedical Engineering, The Chinese University of Hong Kong, NT, Hong Kong, PR China.
PMID: 39149592 DOI: 10.1016/j.bioactmat.2024.07.026
Abstract

A detrimental feedback loop between hypoxia and oxidative stress consistently drives macrophage polarization toward a pro-inflammatory M1 phenotype, thus persistently aggravating rheumatoid arthritis (RA) progression. Herein, an enzyme-catalyzed nanoplatform with synergistic hypoxia-relieving and Reactive Oxygen Species (ROS)-scavenging properties was developed using bovine serum albumin-bilirubin-platinum nanoparticles (BSA-BR-Pt NPs). Bilirubin was employed to eliminate ROS, while platinum exhibited a synergistic effect in scavenging ROS and simultaneously generated oxygen. In mice RA model, BSA-BR-Pt NPs treatment exhibited superior effects, resulting in significant improvements in joint inflammation, cartilage damage, and bone erosion, compared to methotrexate, the most widely used antirheumatic drug. Mechanistically, RNA-sequencing data and experimental results elucidated that BSA-BR-Pt NPs induced a re-polarization of hypoxic M1 macrophages to M2 macrophages via switching glycolysis to Oxidative Phosphorylation through the inhibition of HIF-1α pathway. Collectively, this research for the first time elaborated the underlying mechanism of enzyme-catalyzed nanoplatform in orchestrating macrophage polarization, and identified a novel therapeutic strategy for RA and Other inflammatory disorders.

Keywords

Hypoxia; Macrophage; Metabolic regulation; Nanoplatform; Oxidative stress; Rheumatoid arthritis.

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