Microenvironment-Triggered Sequentially Targeted Micelles for Dual Regulation of Macrophages and Fibroblast-Like Synoviocytes via ROS-Responsive Rg1 Release and HAP-1-Mediated Celastrol Delivery in Rheumatoid Arthritis Therapy.

Abstract

Introduction Excessive proliferation of invasive fibroblast-like synoviocytes (FLS) and persistent synovial inflammation inevitably drive the pathological progression of rheumatoid arthritis (RA). A drug delivery system enabling dual regulation of macrophages and FLS is highly desirable for RA treatment. Methods We fabricated microenvironment-triggered sequentially targeted micelles (HAP@CMR) co-loaded with ginsenoside Rg1 (Rg1) and celastrol (Cel) for dual regulation of macrophages and FLS. Rg1 was conjugated to the micelle surface via a ROS-responsive linker. Within the ROS-overexpressing joint microenvironment, ROS-triggered cleavage of the Rg1 shell unmasked the HAP-1 targeting peptide to facilitate FLS endocytosis alongside selective Rg1 release, which suppressed macrophage-mediated inflammation. Cel was selectively internalized by FLS through the exposed HAP-1 peptide to inhibit FLS proliferation. Results In vitro, HAP@CMR repolarized macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, suppressed inflammatory cytokine secretion, and exerted potent inhibitory effects on the proliferation, migration, and invasion of FLS. In a rat collagen-induced arthritis (CIA) model, administration of HAP@CMR led to the most pronounced reduction in paw swelling among all drug-treated groups. Further histological, X-ray, and micro-CT assessments confirmed that this treatment effectively alleviated synovial inflammation, attenuated cartilage erosion, and inhibited bone destruction. Conclusion This novel nanoplatform promotes FLS apoptosis while mitigating local inflammatory responses, providing a promising therapeutic strategy for RA.