Targeting Nonclassical Monocytes via Artificial Cell-Microneedles for Precision Psoriasis Therapy

Current therapies for inflammatory skin diseases predominantly rely on broad systemic immunosuppression and lack precision toward defined immune-cell subsets. Here, we identify CX3CR1⁺ nonclassical monocytes (NCMs) as an inflammatory monocyte subset that contributes to the amplification of psoriasiform inflammation, as supported by integrated analyses of human single-cell transcriptomics, genetic depletion, and adoptive-transfer models. To preferentially engage these disease-associated NCMs, we engineer an artificial cell-microneedle platform, termed CX3@GUV-DMF, comprising CX3CL1-functionalized, drug-loaded giant unilamellar vesicles (GUVs) embedded within a dissolvable hyaluronic acid (HA) microneedle array. Following intradermal insertion, surface-presented CX3CL1 actively navigates GUVs to pathogenic CX3CR1⁺ NCMs, facilitating the targeted, sustained release of the loaded drug. In vivo evaluations and transcriptomic profiling demonstrate that this localized immunomodulatory strategy attenuates inflammatory myeloid activation, neutrophil infiltration, and Th17-associated responses while promoting restoration of epidermal barrier-associated programs. These findings establish a materials-enabled strategy for subset-oriented immune modulation and local inflammatory-niche remodeling, advancing inflammatory skin therapy beyond nonspecific immunosuppression.