A multifunctional nanomaterial attenuates uveitis by suppressing microglial activation and JAK2-STAT1 signaling pathway

Uveitis is a vision-threatening disease. While existing therapies can partially control the condition in many patients, they are often associated with substantial adverse events. Safer and more effective therapeutic strategies are necessary. To investigate the therapeutic potential of TPT nanomicelles (TPTN), a multifunctional amphiphilic nanomaterial, in uveitis and to elucidate its underlying mechanisms. The biocompatibility and bioactivity of TPTN were characterized in vitro. The therapeutic efficacy of TPTN was evaluated in an experimental autoimmune uveitis (EAU) mouse model. Retinal inflammation, blood-retinal barrier (BRB) integrity, and microglial activation were assessed by clinical scoring, histology, immunofluorescence, and Western blotting. To underscore the key signaling pathway targeted by TPTN, we performed integrative proteomic analysis and following validation. TPTN exhibited potent ROS-scavenging capacity and low cytotoxicity. In vivo, TPTN administration markedly alleviated retinal inflammation, attenuated BRB disruption, and inhibited microglial activation in EAU mice. Mechanistically, integrated proteomic and biochemical analyses revealed TPTN’s inhibition of the JAK2–STAT1 signaling pathway. Integrated proteomic, GSEA, PPI, and biochemical analyses indicated suppression of JAK2–STAT1 signaling following TPTN treatment. Pharmacological inhibition of JAK2 with Fedratinib reproduced several therapeutic effects of TPTN, further supporting the involvement of JAK2 signaling in EAU. Taken together, our findings position TPTN as a promising nanotherapeutic agent for uveitis and provide insights into the molecular mechanisms responsible for its therapeutic action.