Hyaluronic acid microneedle patch for transdermal delivery of naringin-loaded PEGylated terpesomes in a rat model of rheumatoid arthritis: Modulation TGF-β1, oxidative stress, and inflammation

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that causes progressive joint damage and systemic effects. Naringin (NRG), a citrus-derived flavonoid with potent anti-inflammatory and antioxidant activities, is hindered by poor solubility and low bioavailability in clinical applications. NRG was encapsulated into PEGylated terpesomes (TPs) prepared by thin-film hydration using phosphatidylcholine, terpenes, and sodium deoxycholate, then integrated into hyaluronic acid–based microneedles (NRG-TPs/HA-MNs) to create a dual-mechanism transdermal delivery system. Optimized NRG-loaded terpesomes possessed a nanoscale particle size (218 ± 0.67 nm), a narrow polydispersity index (PDI: 0.32 ± 0.05), a high entrapment efficiency (79 ± 0.23%), and strong colloidal stability (Zeta potential: −36.37 ± 0.87). HA-MN patches exhibited remarkable mechanical strength, high drug loading (>93%), and successful skin penetration. NRG release was sustained for over 48 h, and transdermal permeation was significantly improved compared to free NRG in both in vitro and ex vivo studies. In a Complete Freund's Adjuvant–induced RA rat model, NRG-TPs/HA-MNs significantly reduced paw edema and joint swelling, preserved joint architecture on X-ray imaging, and ELISA analysis indicated significant decreases in inflammatory mediators TNF-α, IL-1β, IL-6, NF-κB, and MMP-3. qPCR analysis of the genes MYD88, TXNIP, and BCL-2 showed the therapeutic potential of this system, accompanied by decreased levels of the oxidative stress marker malondialdehyde (MDA), suggesting modulation of the mTOR signaling pathway. Elevated transforming growth factor-β expression and histopathology confirmed cartilage protection and tissue repair. NRG-terpesomal incorporated into the HA-microneedle system provides a minimally invasive therapeutic platform for the sustained release of drugs with improved permeation in the treatment of Rheumatoid arthritis.