Engineered Protein Nanoparticles Enable Targeted Topical Delivery of Upadacitinib for Enhanced Arthritis Therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder driven by persistent synovial inflammation and leading to joint destruction. Although the Janus kinase (JAK) inhibitor upadacitinib (UPA) is clinically effective, its systemic administration is associated with dose-limiting toxicities and poor patient adherence, highlighting an urgent need to minimize systemic exposure. Topical application offers a promising route for targeted joint delivery, but its efficacy is hampered by the formidable skin barrier and the poor retention of conventional formulations. To overcome these challenges, we developed a protein-based nanoparticle system by assembling engineered protein K72 with carboxylate-terminated poly(ethylene glycol) (PEG-COOH) to encapsulate UPA. This design significantly enhanced nanoparticle stability, drug loading capacity, and transdermal penetration efficiency. The engineered nanoparticles demonstrated sustained drug release and superior skin penetration. In a collagen-induced arthritis (CIA) mouse model, topical application of these nanoparticles achieved pronounced therapeutic efficacy against RA progression, with no observable systemic toxicity. This work establishes a safe, convenient, and highly effective topical nanoplatform for the local management of RA.