Manganese-Based Immunomodulatory Nanocomposite with Catalase-Like Activity and Microwave-Enhanced ROS Elimination Ability for Efficient Rheumatoid Arthritis Therapy

Rheumatoid arthritis (RA) is a chronic autoimmune disease commonly associated with the accumulation of hyperactive immune cells (HICs), particularly macrophages of pro-inflammatory (M1) phenotype, accompanied by the elevated level of reactive oxygen species (ROS), decreased pH and O2 content in joint synovium. In this work, an immunomodulatory nanosystem (IMN) is developed for RA therapy by modulating and restoring the function of HICs in inflamed tissues. Manganese tetraoxide nanoparticles (Mn3O4) nanoparticles anchored on UiO-66-NH2 are designed, and then the hybrid is coated with Mn-EGCG film, further wrapped with HA to obtain the final nanocomposite of UiO-66-NH2@Mn3O4/Mn-EGCG@HA (termed as UMnEH). When UMnEH diffuses to the inflammatory site of RA synovium, the stimulation of microwave (MW) irradiation and low pH trigger the slow dissociation of Mn-EGCG film. Then the endogenously overexpressed hydrogen peroxide (H2O2) disintegrates the exposed Mn3O4 NPs to promote ROS scavenging and O2 generation. Assisted by MW irradiation, the elevated O2 content in the RA microenvironment down-regulates the expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha). Coupled with the clearance of ROS, it promotes the re-polarization of M1 phenotype macrophages into anti-inflammatory (M2) phenotype macrophages. Therefore, the multifunctional UMnEH nanoplatform, as the IMN, exhibits a promising potential to modulate and restore the function of HICs and has an exciting prospect in the treatment of RA. The authors have successfully developed a hierarchical and multifunctional UMnEH nanoplatform as the immunomodulatory nanosystem (IMN). Assisted by MW irradiation, UMnEH can significantly increase the oxygen content and then down-regulate the expression of HIF-1 alpha, accompanied by the clearance of reactive oxygen species (ROS) to achieve the polarization of macrophages from M1 to M2 phenotype, which has exciting prospects in the treatment of RA. image