Engineering autoimmune disease models using organoids: Harnessing microenvironmental engineering for precision medicine and immunological recapitulation

Abstract Autoimmune diseases—including systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA)—are increasingly understood as programmable microenvironmental states, wherein evolving changes in matrix mechanics, barrier integrity, interferon and cytokine networks, immune‐complex deposition, and stromal–immune reciprocity progressively reshape tissue behavior. These shifting axes generate nonlinear trajectories of fibrosis, vascular injury, and joint destruction that static or reductionist in vitro systems fail to recapitulate. Organoid and organ‐on‐a‐chip platforms now allow controlled reconstruction of these dynamic microenvironments in human‐derived systems. By integrating iPSC‐derived epithelial, endothelial, stromal, and immune lineages with tunable extracellular matrix (ECM) stiffness and viscoelasticity, perfusable microvasculature, and modular innate and adaptive immune components, these systems reproduce key autoimmune phenomena. These include stiffness‐driven fibroblast activation and endothelial‐to‐mesenchymal transition (EndoMT), interferon‐conditioned barrier collapse, immune‐complex‐mediated injury, and cytokine‐dependent stromal invasion. Patient‐specific induced pluripotent stem cell (iPSC), CRISPR‐based editing of risk alleles, and controlled exposure to sera or autoantibody repertoires provide genetic and immunologic personalization, while multi‐omic profiling, spatial imaging, and machine‐learning analytics enable quantitative alignment between organoid states and patient tissues. By translating pathogenic microenvironmental logic into controllable 3D systems, these platforms establish autoimmune organoids as programmable, human‐relevant tools for mechanistic discovery, therapeutic interrogation, and precision modeling—laying the groundwork for next‐generation, potentially animal‐free pipelines and advancing personalized immunology across SSc, SLE, and RA.