pH-Responsive Cinnamaldehyde-Arginine Nanoprodrug for Targeted Rheumatoid Arthritis Therapy via Antioxidant Activity and Macrophage Reprogramming.

Conventional therapies for rheumatoid arthritis (RA) are limited by poor selectivity, insufficient modulation of the oxidative inflammatory microenvironment, and systemic side effects. Oxidative stress and macrophage-driven immune dysregulation represent critical therapeutic targets. Cinnamaldehyde (CA) and arginine (Arg) possess antioxidant, anti-inflammatory, and anti-osteoclastogenic activities, but their poor solubility, instability, and lack of targeting restrict clinical application. Here, we report a pH-responsive cinnamaldehyde-arginine nanoprodrug (Arg-CA NPs), synthesized via Schiff base reaction, that spontaneously self-assembles into uniform nanoparticles capable of acid-triggered dual-drug release. Arg-CA NPs enhanced the solubility and stability of CA, exhibited excellent dispersibility and circulatory stability, and demonstrated intrinsic antioxidant and anti-inflammatory properties. Mechanistically, Arg-CA NPs attenuated intracellular ROS accumulation, preserved mitochondrial function, and reprogrammed macrophages toward an anti-inflammatory M2 phenotype by suppressing hypoxia-inducible factor-1α (HIF-1α), cyclooxygenase-2 (COX-2), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. In an adjuvant-induced arthritis (AIA) rat model, Arg-CA NPs selectively accumulated in inflamed joints and significantly alleviated joint swelling, synovial inflammation, cartilage erosion, and bone destruction. These findings identify Arg-CA NPs as a promising redox-active nanoplatform for RA therapy by targeting oxidative stress and immune dysregulation.