Synergy of dissolving microneedles and ultrasound to enhance transdermal delivery for rheumatoid arthritis.

Dissolving microneedles (DMNs) are an emerging transdermal drug delivery system that has gained increasing attention as an alternative to traditional oral and injectable methods for treating rheumatoid arthritis (RA). However, these DMNs encounter challenges related to insufficient drug diffusion through passive mechanisms. To address this issue, we developed biocompatible DMNs fabricated from hyaluronic acid (HA) loaded with ultrasound-responsive nanoparticles, aiming at enhancing drug permeation and diffusion through ultrasound (US) assistance. Methotrexate (MTX), a first-line treatment for RA, was encapsulated in poly (lactic-co-glycolic acid) (PLGA)-based nanoparticles containing perfluoro-n-pentane (PFP), referred to as MTX-PFP-NPs. These nanoparticles were then incorporated into DMNs, designated as MTX-PFP-NPs@DMNs. Under the cavitation effect of ultrasound, PFP undergoes a phase transition that facilitates drug release and diffusion. The synergistic effect of the DMNs system and US were demonstrated in both an ex-vivo rat skin model and a collagen-induced arthritis (CIA) mouse model. The MTX-PFP-NPs@DMNs exhibited sufficient mechanical strength to penetrate the stratum corneum and dissolve completely within 20 min, enabling effective drug delivery. The synergistic effect of the DMNs system and US was evidenced by enhanced FITC penetration and diffusion in the ex-vivo rat skin model. Additionally, in vivo studied showed improved therapeutic efficacy in reducing joint swelling, bone erosion, cartilage damage, and pro-inflammatory cytokines level compared to only MTX-PFP-NPs@DMNs. This research underscores the promising integration of DMNs technology and US, offering a high-compliance approach to transdermal drug delivery that could significantly improve treatment outcomes for chronic conditions like RA.