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

ABSTRACT 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.