A Boron-Doped Copper Single-Atom Nanozyme Ameliorates Atopic Dermatitis Via Dual Regulation of Thymic Stromal Lymphopoietin Signaling and Receptor Interaction

Abstract Atopic dermatitis (AD) is a chronic inflammatory skin disorder in which keratinocyte (KC)-derived thymic stromal lymphopoietin (TSLP) orchestrates pathogenic crosstalk between epithelial cells and immune cells. Here, we present a boron-doped copper single-atom nanomaterial (Cu/NC-B) designed to achieve a dual functional blockade of the TSLP signaling axis, offering a more comprehensive therapeutic intervention. Therapeutically, Cu/NC-B significantly alleviated MC903-induced AD-like lesions, showing efficacy comparable to that of crisaborole (CB) with a superior safety profile. Single-cell transcriptomics analysis revealed that Cu/NC-B selectively targets a previously uncharacterized, highly inflammatory KC subpopulation (KC_Spinous_Tslp), thereby disrupting a critical cellular node in AD pathology. At the molecular level, Cu/NC-B exerts its effects through two complementary pathways: epigenetic repression of TSLP via nicotinamide adenine dinucleotide (NAD+)-dependent activation of SIRT1/3 and competitive antagonism of the TSLP receptor (TSLPR). Our work establishes Cu/NC-B as a dual-action nanotherapeutic capable of concurrently suppressing TSLP transcription and disrupting its receptor engagement, thereby proposing a targeted intervention for AD treatment.