Microneedle patches deliver targeted GLP-1RAs-loaded nanoparticles for the treatment of rheumatoid arthritis.

Despite the strong immune-modulatory benefits, there has been a lag in using glucagon-like peptide-1 receptor agonists (GLP-1RAs) in rheumatoid arthritis (RA) due to inefficient articular delivery and poorly understood direct cartilage protection. In this paper, we addressed these critical issues through the mechanism-informed design of a hierarchical drug delivery system. We elucidated previously unnoted ways in which GLP-1RAs curbed RA pathology via direct suppression of the cGAS-STING signaling pathway to inhibit chondrocyte ferroptosis and concomitantly induced macrophage M2 polarization. To turn this mechanistic insight into a targeted therapy, we developed cartilage-targeting silk fibroin nanoparticles modified with a type II collagen-binding peptide WYRGRL for localized GLP-1RAs delivery (GLP-1RAs@NPs-WYRGRL). These GLP-1RAs@NPs-WYRGRL were subsequently loaded into dissolving microneedles (MNs) patches, giving a composite MNs/GLP-1RAs@NPs-WYRGRL system. This system enabled painless transdermal delivery with marked accumulation in arthritic joints, which effectively inhibited chondrocyte ferroptosis via the aforementioned mechanism and also promoted macrophage M2 polarization, thereby attenuating RA progression. This study not only found that the cGAS-STING-ferroptosis pathway was a druggable target in joints, but also pioneered a new flexible delivery platform that resolved the key limitation of low local drug concentrations in joints after systemic administration, and offered a cartilage-protecting perspective for RA.