Trophoblast Extracellular Vesicles Rewire Immunity: A Symptom‐Relief Avenue for Recessive Dystrophic Epidermolysis Bullosa

ABSTRACT Redirecting immune responses toward tissue repair represents a promising strategy for treating inflammatory and degenerative diseases. Extracellular vesicles (EVs), derived from allogeneic stem cells, have shown potential for modulating proinflammatory immunity. Among these, placental‐derived EVs (PEVs) are emerging as candidates for immune‐mediated inflammatory disorders due to their role in establishing maternal immune tolerance. However, their applicability beyond pregnancy remains limited by key translational barriers, including the lack of a standardized and scalable source system and need to demonstrate immunomodulatory activity in non‐pregnancy allogeneic contexts. In this study, we identify extravillous trophoblasts (EVTs), which play critical role in early placental development, as key source of immunoregulatory PEVs. To overcome donor variability, we employed the HIPEC cell model as established surrogate for primary EVTs and assessed the effects of their derived EVs (EVT‐EVs) on circulating monocytes, pivotal mediators of inflammatory responses. High‐dimensional molecular profiling revealed that EVT‐EVs, similar to EVs derived from first‐trimester primary human trophoblast, carry a distinctive anti‐inflammatory signature, including a unique miRNA repertoire enriched in immunoregulatory pathways. Integrated proteomic and lipidomic analyses demonstrated that EVT‐EVs induce coordinated functional reprograming of monocytes toward an immunomodulatory, inflammation‐resolving phenotype. Notably, EVT‐EVs also modulated the inflammatory bias of monocytes from patients with recessive dystrophic epidermolysis bullosa (RDEB), a genetic disorder characterized by chronic inflammation, thereby promoting restoration of immune balance. Collectively, these findings identify EVT‐EVs as a scalable, off‐the‐shelf platform with high translational potential for the treatment of chronic inflammatory diseases.