Transdermal microneedle integrating a biomimetic self-enhancing Fenton reaction nano-reactor for alleviating rheumatoid arthritis by inflammatory microenvironment remodeling

<b>Rationale:</b> Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and persistent inflammation in multiple joints is an important sign for the progression of RA. To this end, we developed the transdermal microneedle integrating biomimetic self-enhancing Fenton reaction nano-reactor, for the purposes of eliminating reactive oxygen species, reducing hypoxia and inflammation, and regulating macrophage phenotype. <b>Methods:</b> A novel biomimetic self-enhanced Fenton reaction nano-reactor was synthesized using an M1 macrophage cell membrane-coated tannic acid-modified iron oxide nanoparticle (IO-NH₂-TA TNPs@M1). The regulatory mechanisms of the IO-NH₂-TA TNPs@M1 were investigated by evaluating ROS scavenging, degree of hypoxia, adsorption of pro-inflammatory factors, and M2 macrophage polarization. Then, the nano-reactor was incorporated into a dissolving microneedle, utilizing enzyme-cut oligomeric sodium hyaluronate, and subsequently assessed for pharmacodynamics and safety. <b>Results:</b> <i>In vitro</i> mechanisms of IO-NH₂-TA TNPs@M1 included eliminating ROS, inhibiting the expression of HIF-1α, decreasing the content of pro-inflammatory factors (IL-6 and TNF-α), and inducing macrophage M2 polarization. Pharmacodynamic and <i>in vitro</i> mechanistic studies showed that IO-NH₂-TA TNPs@M1DM maximally alleviated joint swelling and fever, protected joint cartilage, improved the local hypoxia environment and promoted macrophage M2 polarization. Cytotoxicity assays and HE staining showed that IO-NH₂-TA TNPs@M1DM displayed good biocompatibility. <b>Conclusions:</b> This study designed and synthesized an innovative biomimetic self-enhancing Fenton reaction nano-reactor, and utilized microneedles for the transdermal delivery, providing a scientific and effective new strategy for the precise treatment of RA.