Tissue-derived extracellular vesicles-mediated delivery of a hepatic enzyme living panorama (HELP) for treating multifactorial liver diseases.

Abstract

BACKGROUND: Dysregulation of hepatic drug-metabolizing enzymes is a hallmark of liver injury and contributes to treatment failure. Current strategies often overlook the complexity of the integrated enzyme network. This study reports the use of tissue-derived extracellular vesicles (TEV) as a novel bioinspired delivery platform for a functional hepatic enzyme living panorama (HELP)-a synergistic ensemble of key drug-metabolizing enzymes including cytochrome P450 (CYP450), UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and glutathione S-transferase (GST) families. RESULTS: We isolated TEV from liver tissue and demonstrated their enrichment in functional cytochrome P450s, UGTs, SULTs, and GSTs via proteomics. TEV exhibited robust metabolic activity in vitro and ex vivo. In murine models of acute liver failure, alcoholic liver disease, and metabolic dysfunction-associated steatotic liver disease, TEV administration improved survival, attenuated liver injury, and restored enzyme function without altering host gene expression-confirming direct enzyme delivery. TEV also synergized with conventional therapeutics (regorafenib, silymarin), enhancing efficacy while reducing toxicity. Notably, TEV conferred protection in vulnerable populations with inherent enzymatic deficiencies (neonates, aged mice). CONCLUSIONS: TEV serve as an effective platform for functional enzyme delivery, restoring hepatic metabolic capacity across diverse injury models and special populations. This study introduces HELP as a novel therapeutic strategy for liver diseases characterized by enzymatic dysfunction.