Deep eutectic solvents (DES) have demonstrated their ability to facilitate skin penetrability of rigid nanoparticles (NPs). Here, we reported a feasible and simple transdermal delivery strategy using mesoporous silica nanoparticles impregnated in DES hydrogels for topical management of rheumatoid arthritis (RA). To achieve this goal, nanoceria was immobilized within a silica nanoparticle matrix (MSN) and encapsulated with methotrexate (MTX). The functionalized nanoparticles were first engineered in an Arginine (Arg)-citric acid (CA) DES and then transferred to the carbomer hydrogel matrix. Due to the strong affinity of DES hydrogels to the skin, combined with solvent-driven “Drag” effects, the prepared DES-MSN hydrogels produced dynamic mobility of MSNs through skin layers, resulting in high skin penetrability. After application to the skin, the hydrogel solvent drove the rigid NPs across the skin barrier in a nonintrusive manner, resulting in sustained penetration and accumulation of MSNs at subcutaneous inflammation sites. Subsequently, the MTX payload exerted a direct therapeutic effect, while nanoceria moderated the inflammatory microenvironment by initiating reactive oxygen species (ROS) scavenging and transformation of the macrophage phenotype. In this way, the synergistic action of the combination of immuno- and chemotherapy of the drug and its carrier on RA was achieved. Our work provides a novel strategy for multisite regulation and controlled management of RA in a noninvasive way.
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