A Caspase-3 responsive nanoemulsion for targeted treatment of rheumatoid arthritis through dual modulation of inflammation and mitochondrial dysfunction.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, pain, and progressive joint damage. Current treatments, while effective, are limited by their potential side effects, particularly in long-term use. This study introduces a novel nanoemulsion-based therapeutic approach combining rapamycin, an mTOR inhibitor, with SS31, a mitochondrial-targeting antioxidant peptide. The rapamycin-SS31 conjugate (RS31) is encapsulated within a nanoemulsion (RS31@NEs) designed to selectively release its components in response to elevated Caspase-3 levels, prevalent in inflamed joints. In vitro and in vivo studies using zymosan-induced arthritis (ZIA) and collagen-induced arthritis (CIA) mouse models demonstrated that RS31@NEs effectively reduced pro-inflammatory cytokines, mitigated oxidative stress, and improved immune modulation by enhancing regulatory T and B cell functions. These findings highlight RS31@NEs as a promising dual-action therapy for RA, combining anti-inflammatory and mitochondrial protective effects while minimizing systemic toxicity.