Topical ionic liquid-mediated GLUT1 gene editing ameliorates psoriasis and prevents recurrence.

Abstract

Psoriasis is a chronic inflammatory skin disorder characterized by immune dysregulation and a high relapse rate. Current therapies seldom achieve lasting remission. Aberrant overexpression of glucose transporter 1 (GLUT1) in keratinocytes enhances glycolysis, fueling inflammation and immune imbalance, thus positioning GLUT1 as a promising therapeutic target. In this work, a composite ionic liquid-mediated transdermal platform was established for the delivery of CRISPR-Cas9 ribonucleoprotein (CIL-RNP), aiming to achieve efficient GLUT1 gene editing in keratinocytes. The CIL-RNP achieved 76.6% editing efficiency, downregulated pyruvate kinase M (PKM) expression, and reduced inflammatory cytokine secretion. In a psoriasis mouse model, topical administration of CIL-RNP decreased lesion severity by 50% PASI (Psoriasis Area and Severity Index) score, alleviating epidermal hyperplasia and immune infiltration. Furthermore, the treatment inhibited M1 macrophage polarization, reduced reactive oxygen species generation, rebalanced Th17/regulatory T cells (Tregs) responses, and diminished the accumulation of tissue-resident memory T cells (TRMs), thereby lowering the risk of relapse. This study establishes ionic liquid-based CRISPR-RNP transdermal editing of GLUT1 as a novel and effective strategy for restoring immune homeostasis in psoriasis, with potential for long-term remission and broader applications in cutaneous immunopathological conditions.