“Don't‐eat‐me” Signal Blockade With Engineered Extracellular Vesicles Platform for Acute Liver Failure

Acute liver failure (ALF) is a fatal syndrome in which necrotic hepatocytes evade immune clearance by upregulating CD47. Although CD47‐blocking antibodies show promise, their clinical translation is challenged by systemic toxicity and manufacturing limitations. To address this unmet clinical need, we develop a targeted, cell‐free immunotherapy platform based on signal regulatory protein α (SIRPα)‐engineered extracellular vesicles (SIRPα‐EVs) specifically designed for ALF treatment. Primary human mesenchymal stromal cells (MSCs) are genetically modified to stably overexpress SIRPα, enabling the production of clinical‐grade, high‐purity SIRPα‐EVs in a 3D microcarrier‐based bioreactor. Intravenous injection of SIRPα‐EVs results in preferential accumulation in CD47‐upregulated injured liver tissue, where surface‐exposed SIRPα antagonizes CD47 signaling and promotes macrophage‐mediated clearance of necrotic cells. In the ALF model, SIRPα‐EVs improve survival rates, reduce liver fibrosis, and promote liver regeneration. This study establishes an engineered EV platform as a scalable, targeted therapeutic strategy for ALF, bridging the gap between mechanism‐driven nanomedicine and clinical hepatology.