Intradermal delivery of nanohybrid thermosensitive hydrogels loaded with chondroitin sulphate coated pomegranate lipid carriers via hollow microneedles for effective rheumatoid arthritis management

Rheumatoid Arthritis (RA) is a common inflammatory arthritis type that significantly affects physical functions, leading to restrictions in daily activities. The current study aims to develop an effective nano-based drug delivery system for RA management using pomegranate peel extract (POM). POM was encapsulated in nanostructured lipid carriers (NLCs), coated with chondroitin sulphate (CHS) to actively target CD44 receptors that are over expressed in rheumatic joints. The optimized NLCs were loaded into Pluronic F127 hydrogels to prepare thermosensitive nanohybrid hydrogels for intradermal administration via AdminPenTM MNs hollow microneedles (Ho-MNs). The UPLC-ESI-MS/MS analysis of POM identified 76 compounds, predominantly polyphenols, known for anti-inflammatory and antioxidant properties. NLCs were prepared using the melt emulsification method, showing particle sizes ranging from 64.7 f 0.34 to 341 f 2.5 nm, zeta potentials between -17 f 1.34 mV and -30 f 0.98 mV, and high entrapment efficiencies (96.34 f 0.34-98.89 f 0.12 %). Nanohybrid hydrogels extended the release period of POM from 6 days to 13 days and reduced burst effects. Ex vivo studies confirmed effective skin penetration by AdminPenTM MNs. In vivo studies in rats with AIA demonstrated that POM nanohybrid hydrogels significantly relieved joint swelling and reduced TNF-alpha, IL-1 beta, MDA, and MMP-3 levels, while increasing NRF2 level. Histopathological examination revealed that the nanohybrid hydrogel-treated group had normal joint and cartilage structure. This novel system offers a minimally invasive, sustained-release approach for RA treatment, enhancing bioavailability and the therapeutic efficacy of POM, thus providing a promising alternative to conventional therapies.