Weimin Sun

and 11 more

Background: Reducing the number of airway eosinophils is critical for treating eosinophilic asthma. The JAK2-STATs pathway is essential for myelopoiesis of eosinophils and production of type I and II cytokines, and therefore can be a novel target for intervention of eosinophilic asthma. Here, we aimed to demonstrate the apoptosis-inducing potential of Fedratinib (FDTN), a JAK2-specific inhibitor, and test the efficacy of the ROS-responsive, FcRn-targeting and FDTN-caged nanoparticles on eosinophilic asthma alleviation. Methods: The apoptosis-inducing potential of FDTN in eosinophils from asthma patients was assessed by flow cytometry, and light and electron microscopy. FDTN-caged nanoparticles (NPs-FDTN) were designed to ROS responsive and modified with Fc portion of IgG through the avidin-biotin interaction. The biological availability of NPs-FDTN was assembled via biochemical and immunological analysis, and the therapeutic effects were investigated in eosinophilic asthma model mice by comparing free FDTN and budesonide treatment. Results: FDTN blocked the JAK2/STAT5 pathway and activated the intrinsic pathway of apoptosis in eosinophils in a concentration-dependent manner. NPs-FDTN crossed the epithelial barrier via the Fc/FcRn-mediated transcytosis, bypassed the lysosome and entered the inflammatory microenvironment. Caged FDTN was released from the nanoparticles in the presence of ROS. Compared to free FDTN, the residence time of FDTN in the lung parenchyma was prolonged and the therapeutic effects were improved when delivered in nanoparticles. Conclusion: Ros-responsive, FcRn-targeting and FDTN-caged nanoparticles overcame the airway epithelial barrier and improved the bioavailability on eosinophil apoptosis. This study provides a fancy and safe therapeutic strategy for treatment of eosinophilic asthma.