Glutamine-based Metabolism Normalization and Oxidative Stress Alleviation by Self-assembled bilirubin/V9302 Nanoparticles for Psoriasis Treatment

Psoriasis is an immune-mediated chronic inflammatory skin disorder characterized by epidermal hyperplasia and infiltration of inflammatory cells. Even though the pathogenesis remains unclear, T helper 17 (Th17) cells-mediated inflammation and keratinocyte-involved proliferation are considered to play key roles during the occurrence and the development of psoriasis. Therefore, suppressing the infiltration/function of Th17 and the abnormal hyperplasia of keratinocytes could be a rational strategy for ameliorating and treating psoriasis. In this study, a self-assembly nanoparticle (BVn) was developed with bilirubin (an endogenous antioxidant) and V9302 (a blocker of ASCT2, an amino acid transporter mediating glutamine influx for providing energy and activating mTOR pathway) to intervene the local metabolism and alleviate oxidative stress for psoriasis treatment. BVn effectively suppressed inflammatory keratinocyte proliferation and scavenged excess ROS. In the in vivo psoriasis mouse model, BVn showed increased permeation and delayed retention in the psoriatic lesion and reversed the psoriasis-related symptoms, evidenced by the normalized keratinocyte condition and decreased Th17 infiltration/activation. Mechanism study indicated that BVn not only cut off the energy supply but also suppressed cell proliferation or lymph cell expansion by deactivating mTOR pathway, besides alleviated oxidative stress. BVn-based glutamine metabolism modulation strategy offers a promising strategy for psoriasis therapy. This article is protected by copyright. All rights reserved