3D organotypic skin models recapitulate autoantibody-driven pemphigus pathomechanisms and targeted therapeutic response.

Advanced three-dimensional (3D) tissue models that recapitulate autoimmune disease progression can enable mechanistic studies and accelerate the development of targeted therapies with reduced reliance on systemic immunosuppression. Here, we present a dynamic biofabrication strategy combining 3D bioprinting and cell self-organization to create multilayered skin constructs with a stratified epidermis atop a vascularized, fibroblast-remodeled dermis. This platform reconstitutes native skin architecture to model pemphigus vulgaris, an autoantibody-driven blistering disorder. Tightly reassembled keratinocytes form cell-cell adhesions that replicate pathogenic antibody-induced disruption of the epidermal barrier, while embedded vasculature and fibroblasts shape dermal barriers that regulate molecular diffusion. We demonstrate that these tissue barriers define disease phenotypes and therapeutic responses by modulating antibody and drug penetration. As proof of concept, we quantitatively evaluate epidermal growth factor receptor-targeted inhibitors by measuring individual cell-cell junction integrity and applying machine learning-assisted image texture analysis. This organotypic skin model provides a physiomimetic testbed for precise investigation of autoimmune pathogenesis and high-throughput screening of targeted therapeutic agents.