An ROS-responsive artesunate prodrug nanosystem co-delivers dexamethasone for rheumatoid arthritis treatment through the HIF-1α/NF-KB cascade regulation of ROS scavenging and macrophage repolarization

The signaling cascade between nuclear factor-kappa B (NF -KB) and hypoxia-inducible factor-1 alpha (HIF-1 alpha) can be activated by proinflammatory M1 macrophages in rheumatoid arthritis (RA), which produces reac-tive oxygen species (ROS) and enhances M1 macrophage polarization, thus aggravating the development of RA. Therefore, an ROS-responsive artesunate prodrug micellar nanosystem for co-delivery of dexam-ethasone (DEX/HA-TK-ART micelles, abbreviated as DEX/HTA) was developed for synergistic inhibition of the HIF-1 alpha/NF-KB cascade to regulate ROS scavenging and macrophage repolarization in RA combi-nation therapy. DEX/HTA micelles displayed prolonged circulation in blood and efficiently co-delivered ART&DEX in the inflamed joints of adjuvant-induced arthritis (AIA) rats; moreover, they were specifically recognized and internalized into M1 macrophages through CD44 receptor-mediated endocytosis. ROS-responsive co-released ART&DEX then exerted a synergistic action to efficiently perform ROS scavenging and repolarization of M1 to M2 macrophages by inhibition of the HIF-1 alpha/NF-KB cascade. The intravenous administration of DEX/HTA micelles into AIA rat models significantly alleviated inflammatory cell infiltra-tion and repaired cartilage injury in the joint. Collectively, our study highlights the therapeutic potential of DEX/HTA micelles for treating RA through synergistic inhibition of the HIF-1 alpha/NF-KB signaling cascade to regulate ROS scavenging and macrophage repolarization.Statement of significanceAn ROS-responsive artesunate (ART) prodrug micellar nanosystem for co-delivering dexamethasone (DEX), abbreviated as DEX/HA-TK-ART micelle, was developed for synergistic cascade regulation of the HIF-1 alpha/NF-KB pathway on ROS scavenging and macrophage repolarization in combination therapy for rheumatoid arthritis. The well-designed nanosystem showed prolonged circulation in blood and supe-rior ART&DEX accumulation in the inflamed joints of AIA rats; moreover, the micelles were specifically internalized into M1 macrophages and co-released ART&DEX, subsequently leading to inhibition of the HIF-1 alpha/NF-KB pathway for ROS scavenging and macrophage repolarization, thus generating synergistic anti-inflammatory effects in RAW 264.7 cells and AIA rats. The HIF-1 alpha/NF-KB cascade regulation on ROS scavenging and macrophage repolarization based on ART&DEX combination with smart nanotechnology could serve as a promising approach for rheumatoid arthritis therapy (c) 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Automated summary

This study developed an ROS-responsive artesunate prodrug micellar nanosystem for co-delivering dexamethasone, which synergistically inhibits the HIF-1 alpha/NF-KB signaling cascade in rheumatoid arthritis, regulating ROS scavenging and macrophage repolarization.