Reactive Oxygen and Nitrogen Species – “Nanosweeper” for Rheumatoid Arthritis Theranostics by Macrophage Reprogramming

Excessive reactive oxygen and nitrogen species (RONS) accumulation in joints are significant variables that affect the course of rheumatoid arthritis (RA). Scavenging of RONS to remodel macrophage homeostasis is a potentially powerful treatment for RA. Here, a visualized "nanosweeper" by functionalizing ultrasmall Gd/Fe₃O₄ nanoparticles with thiol-polyethylene glycol-phosphoric acid and 2-(3-(2-aminophenyl)ureido) ethyl methacrylate hydrochloride (APUEMA), namely GIA NPs, can simultaneously scavenge both nitric oxide (NO) and reactive oxygen species (ROS), as well as enhance magnetic resonance imaging (MRI) for the diagnosis and therapy of RA. GIA NPs could not only eliminate NO by reactions between the <i>o</i>-phenylenediamine moieties of APUEMA and NO molecules but also remove ROS by the superoxide peroxidase activities of the Fe₃O₄ nanoparticles and thiol. <i>In vitro</i> and <i>in vivo</i> experiments revealed that the simultaneous scavenging of NO and ROS strategy inhibited the overactivation of the cyclic guanosine monophosphate/protein kinase G (cGMP/PKG) signaling pathway to reprogram the polarization states of macrophages and interfered with metabolism to alleviate RA. In addition, GIA NPs, as dual-modal nanoprobes for MRI, exhibited the capacity for the early diagnosis of RA lesions and monitoring during the RA treatment process. The visualized "nanosweeper" strategy provides a promising integrated platform for the diagnosis and treatment of RA.