NO-responsive microgel encapsulated Ce-MOF nanozymes loaded with gastrodin for synergistic rheumatoid arthritis therapy

A multifunctional nanocomposite, composed of Ga-loaded Ce-MOF core and NO-responsive microgel shell, is designed to integrate effective drug loading, controlled drug release and multi-target synergy to therapy RA. • The Ga-loaded Ce-MOF core functions dually as a high-capacity drug carrier of natural compound and a nanozyme with superoxide dismutase/catalase-like activities for reactive oxygen species (ROS) elimination, effectively alleviating oxidative stress damage in RA and establishing initial synergistic effects with Ga intrinsic anti-inflammatory activity. • The NO-responsive microgel shell acted as pathological cue-triggered “gatekeeper”, enabling on-demand drug release specifically at inflammatory sites while concurrently scavenging excessive NO to synergetic treat RA. • The nanocomposite significantly inhibits pro-inflammatory cytokines, alleviates cartilage degradation and bone erosion by eliminating excessive RONS, promoting the repolarization of macrophages from M1 to M2 phenotypes, and regulating the MAPK and cGMP/PKG signaling pathways. • This “one-stone-three-birds” strategy that integrating natural drug therapy, stimuli-responsive drug release with synergistic RONS scavenging and immune homeostasis modulation, offers an innovative and efficient approach for treatment of RA and other inflammatory diseases. Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent inflammatory injury and progressive destruction of joints. The elimination of excessive reactive oxygen and nitrogen species (RONS) and the restoration of immune homeostasis have emerged as promising therapeutic strategies for RA. Gastrodin (Ga), a bioactive natural constituent derived from Gastrodia elata, possesses inherent antioxidant and anti-inflammatory capacities, whereas its clinical translation and in vivo utility are substantially hampered by inferior environmental stability and uncontrollable drug release behavior. Herein, we fabricated a nitric oxide (NO)-responsive nanocomposite (NCMG) consisted of a Ce-based metal-organic framework (Ce-MOF) nanozyme loaded with Ga and encapsulated by a NO-responsive microgel shell for synergistic RA treatment. The Ce-MOF serves dual functions as a high-efficiency drug carrier and reactive oxygen species (ROS) scavenger, while the outer microgel shell enables precise on-demand Ga release and efficient NO depletion. In vitro experiments and in vivo validation based on adjuvant-induced arthritis (AIA) rat models demonstrated that NCMG markedly inhibits the secretion of pro-inflammatory cytokines, induces macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, and effectively alleviates joint inflammation and bone erosion. Transcriptomic profiling further showed that Ga treatment was associated with downregulation of Il1b and Tnf and alterations in MAPK related gene expression, suggesting the involvement of this pathway in its anti-arthritic activity. This work develops an integrated nanotherapeutic platform combining natural active compounds with multi-component synergistic effects, offering a feasible strategy for RA intervention.