In situ polymeric nanomicelle-generating dissolving microneedle patch for enhanced transdermal methotrexate delivery in rheumatoid arthritis treatment

Rheumatoid arthritis (RA) presents a chronic autoimmune pathology. Methotrexate (MTX), a primary therapeutic agent for RA, often administered orally or via injection, has shown dose-dependent systemic toxicity upon prolonged use. Consequently, a pressing need exists for a secure and facile MTX delivery system in RA management. In the current study, the methoxy poly (ethylene glycol)-poly (lactide) polymer (mPEG-PLA) and hyaluronic acid (HA) were used as materials for both nanomicelles and dissolving microneedles (MNs) to facilitate the effective transdermal delivery of MTX in RA therapy. HA, a specific ligand for the CD44 receptor, could deposit on the outer surface of nanomicelles by interacting with mPEG-PLA, which serve as a targeting ligand for macrophages activated at inflamed joints. Upon MTX-loaded polymeric nanomicelles MNs (MTX@PMs MNs) application to the skin, MNs could effectively puncture the stratum corneum and in situ generate nanomicelles with the dissolution of MNs. In vivo therapeutic efficiency evaluations suggested that the MTX@PMs MNs demonstrated enhanced efficacy in mitigating the progression of RA without inducing treatment-related toxicity. Our findings suggest that the utilization of in situ polymeric nanomicelle-generating dissolving microneedle patches holds promise as a potential strategy for the clinical treatment of RA.