State‐Instructive Apoptotic Body‐Mimetic Nanoparticles Reprogram Macrophages to Establish Antigen‐Specific Immune Tolerance in Celiac Disease

ABSTRACT Celiac disease is an antigen‐driven autoimmune enteropathy characterized by a breakdown of gluten tolerance, yet current antigen‐delivering nanotherapies primarily focus on optimizing nanoparticle properties while overlooking the immunological state of antigen presenting cells (APCs). Here, we engineered apoptotic body‐mimetic gliadin nanoparticles (ABM‐G NPs) by incorporating phosphatidylserine (PS), an endogenous “eat‐me” signal, into a PLGA‐based gliadin delivery platform. ABM‐G NPs enhanced macrophage efferocytosis through PS‐dependent recognition, inducing a tolerogenic macrophage program characterized by metabolic remodeling and epigenetic reprogramming. Mechanistically, ABM‐G NPs promoted glycolytic flux and lactate accumulation, leading to H3K9 lactylation‐mediated activation of immune‐regulatory and metabolic genes, including Mrc1 and Hk1 . In gluten‐induced mouse models of celiac disease, ABM‐G NPs suppressed gliadin‐specific immune responses, promoted regulatory T cell expansion, and alleviated intestinal inflammation. This study establishes a state‐instructive biomaterial strategy that couples apoptotic mimicry with antigen delivery to achieve antigen‐specific immune tolerance.