A Redox-Responsive Nanoplatform Modulating the Treg/Th17 Balance Through LAT1- and PPARγ-Related Pathways for...

Psoriasis is a chronic autoimmune skin disease affecting 2%-3% of the global population. Existing therapies, including topical agents, systemic immunosuppressants, and phototherapy, often suffer from limited efficacy, skin irritation, or serious side effects, highlighting the urgent need for more effective and safer alternatives. Notably, restoring the dynamic balance between regulatory T (Treg) cells and T helper 17 (Th17) cells has emerged as a promising strategy for halting psoriatic progression. Here, we developed a redox-responsive nanoparticle-based topical hydrogel, PB-MJ@N/G, that co-delivers morin (a natural PPARγ activator that promotes Treg proliferation) and JPH203 (a LAT1 inhibitor that suppresses Th17 cell expansion) to modulate the Treg/Th17 balance in psoriatic skin. These drugs were co-loaded into PLA nanoparticles and further coated with bilirubin-conjugated poly-L-lysine (PB), enabling surface charge reversal and promoting local skin association and nanoparticle-associated delivery into psoriatic skin. In response to the oxidative microenvironment, oxidation-associated changes in the bilirubin-containing PB coating increased its hydrophilicity and facilitated accelerated local drug release. In both in vitro and in vivo models, PB-MJ@N significantly restored the Treg/Th17 ratio, alleviated psoriatic inflammation, and attenuated relapse-associated lesion development in a recurrence model. This topical, stimuli-responsive nanoparticle presents a powerful immunotherapeutic strategy for psoriasis, supporting sustained treatment-associated benefit.