The Janus kinase inhibitor tofacitinib (TOF) is an FDA-approved drug for rheumatoid arthritis (RA) treatment, but its long-term oral use leads to significant systemic side effects. The present research aimed to conquer these challenges by formulating hyaluronic-acid-coated transethosomes (HA-TOF-TE), a novel system for targeted, topical delivery of TOF to reduce systemic toxicity and improve therapeutic efficacy. Transethosomes were synthesized via the cold sonication technique with HA functionalization enabling CD44 receptor-mediated targeting of inflamed synovial tissue. Optimized TOF-TE and HA-TOF-TE formulations showed particle sizes of 199.08 ± 4.2 and 151.5 ± 5.4 nm, zeta potentials of -27.1 ± 0.75 and -34.10 ± 0.89 mV, and entrapment efficiencies of 81.16 ± 0.84% and 79.19 ± 2.65%, respectively. The gels were assessed through drug release, permeability, and effectiveness experiments using Freund's complete adjuvant (CFA) model. studies showed 2.02-fold and 1.61-fold increments in flux for TOF-TE and HA-TOF-TE, respectively, with superior skin retention for HA-TOF-TE. efficacy confirmed HA-TOF-TE's significant ( < 0.001) anti-inflammatory effect on arthritic rat paws, outperforming TOF-TE and FD gels. Cytokine analysis showed notable reductions in serum IL-1, IL-6, and PGE-2 levels after HA-TOF-TE treatment, closely approximating control values. Additionally, mRNA analysis demonstrated marked decreases in IL-6, CD44, and collagen II expression, indicating HA-TOF-TE's potential as an effective, targeted RA treatment, addressing the challenges of conventional TOF therapy and minimizing systemic side effects.
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