Confined Cascade Metabolic Reprogramming Nanoreactor for Targeted Alcohol Detoxification and Alcoholic Liver Injury Management

Abstract

Alcoholic liver injury (ALI) is the leading cause of serious liver disease, whereas current treatments are mostly supportive and unable to metabolize alcohol directly. Here we report a metabolic reprogramming strategy for targeted alcohol detoxification and ALI management based on a confined cascade nanoreactor. The nanoreactor (named AA@mMOF) is designed by assembling natural enzymes of alcohol oxidase (AOx) and aldehyde dehydrogenase (ALDH) in the cavity of a mesoporous metal organic framework (mMOF) nanozyme with intrinsic catalase (CAT)-like activity. By conducting confined AOx/CAT/ALDH cascade reactions, AA@mMOF enables self-accelerated alcohol degradation (>0.5 mg·mL-1·h-1) with negligible aldehyde diffusion and accumulation, reprogramming alcohol metabolism and allowing high-efficiency detoxification. Administered to high-dose alcohol-intoxicated mice, AA@mMOF shows surprising liver targeting and accumulation performance and dramatically reduces blood alcohol concentration and rapidly reverses unconsciousness and acute liver injury to afford targeted alcoholism treatment. Moreover, AA@mMOF dramatically alleviates fat accumulation and oxidative stress in the liver of chronic alcoholism mice to block and reverse the progression of ALI. By conducting confined AOx/CAT/ALDH cascade reactions for high-efficiency alcohol metabolism reprogramming, AA@mMOF nanoreactor offers a powerful modality for targeted alcohol detoxification and ALI management. The proposed confined cascade metabolic reprogramming strategy provides a paradigm shift for the treatment of metabolic diseases.