Abstract

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.