Hyaluronic acid-modified PtPdCo-CQ nanocatalyst with triple enzyme-like activities regulates macrophage polarization and autophagy levels for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and imbalanced macrophage polarization. Pro-inflammatory M1 macrophages exacerbate joint damage through excessive production of reactive oxygen species (ROS), while anti-inflammatory M2 macrophages are prone to ferroptosis, limiting the long-term efficacy of existing nanozyme therapies. This study aimed to develop a novel nanocatalyst combining efficient ROS scavenging and M2 macrophage protection to synergistically regulate macrophage polarization and autophagy levels for sustained RA remission. We designed a hyaluronic acid-modified PtPdCo-CQ nanocatalyst (HPPCQ) with triple enzyme-like activities-superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD). In vitro experiments demonstrated that HPPCQ activated the Nrf2/HO-1 antioxidant pathway by scavenging ROS, promoted M1-to-M2 phenotypic repolarization, and protected M2 macrophages from autophagy-dependent ferroptosis via controlled release of chloroquine (CQ). In a collagen-induced arthritis (CIA) mouse model, HPPCQ targeted inflamed joints, significantly reducing clinical scores, synovial hyperplasia, and pro-inflammatory cytokine levels (TNF-α, IL-1β). Histological analysis revealed markedly alleviated cartilage destruction and inflammatory infiltration in HPPCQ-treated mice. By integrating ROS scavenging, macrophage reprogramming, and ferroptosis inhibition, this work provides a novel therapeutic strategy with enhanced efficacy and durability for RA treatment.