A combined “eat me/don’t eat me” strategy based on exosome for acute liver injury treatment

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.