Oxygen-self-supplying biomimetic nanozymes synergize with methotrexate to reprogram macrophage polarization for...

Rheumatoid arthritis (RA) represents a long-term autoimmune condition that affects multiple systems in the body. The primary pathological feature stems from the imbalance in the polarization of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages in the synovial membrane, triggering sequential release of inflammatory factors that drive gradual deterioration of articular structures. This study utilized a biomimetic albumin-inspired nanoreactor approach, where bovine serum albumin (BSA) acted as a dynamic template to guide the multi-stage cooperative self-assembly of cerium oxide and methotrexate (MTX). This process yielded MTX-Ce@BSA nanoparticles demonstrating antioxidant properties, enzyme-like catalytic activity, and the ability to modulate the immune system. Subsequent surface modification using macrophage-derived membranes (MMs) enabled the engineering of MTX-Ce@BSA@MMs (MCB@MMs), a bioinspired nano-carrier system designed for targeted therapeutic delivery. Following cellular uptake, the cerium-based nanozyme demonstrates sequential enzymatic activities mimicking catalase and superoxide dismutase, efficiently neutralizing oxidative stress mediators. Simultaneously, the cerium valence transition between +3 and +4 states promotes molecular oxygen generation, thereby downregulating hypoxia-inducible factor signaling pathways. The gradual liberation of MTX orchestrates anti-inflammatory responses through cytokine profile modification and promotes phenotypic transition of pro-inflammatory macrophages to regenerative subtypes. In a rat model with adjuvant-induced arthritis (AIA), this system significantly reduced joint inflammation and prevented bone erosion, with no signs of systemic toxicity observed. This multidimensional treatment paradigm integrates complementary biological mechanisms, offering a transformative approach to address persistent therapeutic limitations in autoimmune joint disorders. STATEMENT OF SIGNIFICANCE: A biomimetic nanozyme platform (MCB@MMs) was developed to address the limitations associated with conventional disease-modifying antirheumatic drugs (DMARDs) and nano-antioxidants in RA treatment. This platform integrates three key mechanisms: (1) Tandem ROS-scavenging via cerium oxide nanozymes with dual SOD/CAT-mimetic activities, interrupting the ROS-HIF-1α-MAPK pathway; (2) Immunomodulatory synergy between MTX and nanozymes, promoting M1→M2 macrophage transition; (3) Active targeting of inflamed joints via macrophage membrane coating, significantly enhancing accumulation in the synovium. MCB@MMs showed superior efficacy in AIA rats by alleviating symptoms, suppressing bone erosion, and improving hypoxic microenvironments, while maintaining excellent biosafety. This study highlights the synergistic interplay between nanozymes and DMARDs, offering a promising and clinically relevant strategy for the treatment of inflammatory diseases.