A dual-targeted nano-system co-regulating macrophage ROS and fibroblast ferroptosis for rheumatoid arthritis treatment.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a marked macrophage polarization imbalance and abnormal synovial fibroblast proliferation. Herein, we developed a multifunctional drug delivery platform utilizing a glycosaminoglycan heparin derivative. This derivative combines heparin (Hep), which targets macrophages and synovial fibroblasts, with phenylboronic acid (PBA), which exhibits ROS-responsive properties, to regulate macrophage polarization and inhibit synovial fibroblast proliferation. Celastrol (CLT) was encapsulated in multifunctional lipid vesicles (Hep-Lips/CLT) to ameliorate the inflammatory microenvironment. This platform specifically targeted macrophages and synovial fibroblasts, achieving a dual therapeutic effect. Hep-Lips/CLT could serve as an inflammation-targeted therapy, thereby regulating macrophage repolarization, inducing ferroptosis in synovial fibroblasts to inhibit proliferation, and achieving ROS-responsive release. Overall, Hep-Lips/CLT delivery supported by glycosaminoglycan derivatives could be used as a new therapy for RA. Notably, this study presents the first synthetic glycosaminoglycan derivative for preparing multifunctional lipid vesicles to simultaneously target macrophages and synovial fibroblasts, offering an effective RA therapeutic strategy.