A novel ASGR1-Targeting nanocomplex for mitigating donor liver steatosis

• First application of nano-enzymes to fatty liver. • First proposed method to mitigate liver steatosis in the short term. • A new method that can be applied to extended criteria donors. • An effective solution to the lack of targeting of nano-enzymes. • An effective solution to the low bioavailability of ASGR1. Liver transplantation remains the most effective treatment for end-stage liver disease. However, a persistent imbalance between organ supply and demand limits its accessibility, prompting ongoing research to expand the donor pool. As the global prevalence of fatty liver disease rises, so does the number of liver donors with hepatic steatosis. Severely steatotic livers of donors are associated with increased postoperative complications, whereas reducing steatosis in donor livers can improve recipient outcomes and increase donor eligibility. Current anti-steatotic treatments require extended administration, and no rapid-acting solution has yet been developed for steatotic donor livers. Herein, we introduce a novel nanocomplex capable of significantly reducing hepatic steatosis within a short timeframe. This nanocomplex consists of a MIL core containing thyroid hormone, surface-modified with Anti-ASGR1 for targeted delivery. MIL scavenges reactive oxygen species (ROS), while the thyroid hormone accelerates intracellular lipid metabolism. The targeting protein, Anti-ASGR1, specifically binds to hepatic receptors, enhancing intracellular cholesterol processing. The safety and efficacy of this nanocomplex have been rigorously validated in both cellular and animal models. Moreover, in liver transplantation studies, perfusion with the nanocomplex yielded promising results. In summary, this nanocomplex offers a rapid method to reduce hepatic steatosis, facilitating the use of steatotic donor livers, alleviating donor shortages, and potentially benefiting individuals with severe fatty liver disease in the future.