Mesoporous Silica-Based Nanomotors Loaded with Rapamycin for Synergistic Treatment of Rheumatoid Arthritis

Addressing the imbalance between M1 and M2 macrophage phenotypes through the reduction of intracellular oxidative stress represents a promising strategy for treating rheumatoid arthritis (RA). In this study, we developed hydrogen peroxide (H₂O₂)-driven nanomotors, FMn@PMS, specifically targeting M1 macrophages for the precise delivery of rapamycin (Rapa) in RA management. The FMn@PMS nanomotors were synthesized via the in situ growth of manganese dioxide (MnO₂) nanozymes on the surface of polydopamine-hybridized mesoporous silica nanoparticles, followed by surface modification with folic acid to facilitate targeted delivery to M1 macrophages. Rapa-FMn@PMS nanomotors demonstrated injectability for intra-articular administration, alongside prolonged retention and adhesion within the joints, attributable to the catechol groups present in the nanomotors. Furthermore, Rapa-FMn@PMS exhibited superoxide dismutase and catalase mimetic enzyme activities, effectively scavenging excess ROS. Released Rapa activated autophagy to eliminate dysfunctional mitochondria, contributing to the transition of M1 macrophages to M2 macrophages, which modulates the microenvironment of RA and alleviating cartilage damage. Additionally, SiO₄^4- and Mn²⁺ ions released from Rapa-FMn@PMS inhibited osteoclast formation and facilitated cartilage regeneration. The therapeutic efficacy of Rapa-FMn@PMS was validated in antigen-induced arthritis models. In conclusion, this study presents Rapa-FMn@PMS as a multifunctional nanomedicine for rheumatoid arthritis therapy.