A combined “eat me/don’t eat me” strategy based on exosome for acute liver injury treatment
Wei Du, Chen Chen, Yingying Liu, H. U. I. Quan, Ming Xu, Jingjing Liu, Ping Song, Zhiqiang Fang, Z H Yue, Hao Xu, Yu‐Wei Ling, Juanli Duan, Fei He, Lin Wang
Abstract
Drug-induced liver injury (DILI) involves multifaceted pathogenesis, necessitating effective therapeutic strategies. Wnt2, secreted by liver sinusoidal endothelial cell (LSEC), activates the Wnt/β-catenin signaling pathway to promote hepatocyte proliferation after injury. To address the dual challenges of targeted delivery and phagocytosis evasion, we develop a combined “eat me/don’t eat me” strategy. RLTRKRGLK (RLTR) peptide-functionalized exosomes are engineered by inserting DMPE-PEG2000-CRLTRKRGLK into the lipid membrane of exosome derived from bEnd.3 cell. Surface-displayed RLTR mediates exosomal enrichment in LSEC, while CD47 engineering reduces macrophage clearance via “don’t eat me” signaling. Then, lentiviral transfection enables stable encapsulation of functional Wnt2 mRNA into Exo CD47 (designated Wnt2@Exo CD47 ). In both acetaminophen (APAP) and dimethylnitrosamine (DMN)-induced murine liver injury models, RLTR-Wnt2@Exo CD47 demonstrates LSEC-specific targeting and significant hepatoprotection. This engineered exosome platform provides a therapeutic strategy for DILI. • RLTRKRGLK surface modification enables LSEC-targeted exosome delivery • CD47 engineering reduces macrophage clearance via “don’t eat me” signaling • RLTR-Wnt2@Exo CD47 attenuates liver necrosis and enhances regeneration Du et al. develop an exosome-based dual-targeting platform integrating “eat me/don’t eat me” strategies. By combining LSEC-directed RLTRKRGLK ligand display with CD47-mediated phagocytic evasion, this system enables precise Wnt2 mRNA delivery to liver sinusoidal endothelia, effectively ameliorating drug-induced acute liver injury and enhancing hepatic regeneration.