Multifunctional Nanoplatform for Mild Microwave-Enhanced Thermal, Antioxidative, and Chemotherapeutic Treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is usually associated with excessive proliferation of M1-type proinflammatory macrophages, resulting in severe hypoxia and excess reactive oxygen species (ROS) in the joint cavity. Inhibiting M1-type proinflammatory macrophages and/or repolarizing them into M2 phenotype anti-inflammatory cells by alleviating hypoxia and scavenging ROS could be a promising strategy for RA treatment. In this work, a microwave-sensitive metal-organic framework of UiO-66-NH₂ is constructed for coating a nanoenzyme of cerium oxide (CeO₂) and loading with the drug celastrol (Cel) to give UiO-66-NH₂/CeO₂/Cel, which is ultimately wrapped with hyaluronic acid (HA) to form a nanocomposite UiO-66-NH₂/CeO₂/Cel@HA (UCCH). With the microwave-susceptible properties of UiO-66-NH₂, the thermal effect of microwaves can eliminate the excessive proliferation of inflammatory cells. In addition, superoxide-like and catalase-like activities originating from CeO₂ in UCCH are boosted to scavenge ROS and accelerate the decomposition of H₂O₂ to produce O₂ under microwave irradiation. The nonthermal effect of microwaves could synergistically promote the repolarization of M1-type macrophages into the M2 phenotype. Accompanied by the release of the anti-RA chemotherapeutic drug Cel, UCCH can efficiently ameliorate RA in vitro and in vivo through microwave-enhanced multisynergistic effects. This strategy could inspire the design of other multisynergistic platforms enhanced by microwaves to exploit new treatment modalities in RA therapies.