Biomimetic Nanomedicines Deliver Naringin for Enhanced Acute Liver Failure Therapy via Balanced Regulation of Hepatocyte Oxidative Stress and Kupffer Cell Inflammation

Abstract Drug‐induced acute liver failure (ALF) is characterized by rapid hepatocyte necrosis caused by oxidative stress and Kupffer cell (KC)‐mediated inflammation, with limited therapeutic options due to narrow treatment windows. To target this challenge, a biomimetic nanomedicine (RBLN) is developed for balanced drug delivery to both hepatocytes and KCs. Layered double hydroxide nanoparticles (clinically used as Talcid) are loaded with the antioxidant naringin and then coated with red blood cell membranes in fresh (fRBLN) or senescent (sRBLN) states, leveraging the preferential clearance of senescent red blood cells by KCs. This cell membrane coating enabled fRBLN to evade KC clearance and target hepatocytes, while sRBLN is selectively internalized by KCs. Intravenous administration of a 1:1 combination of fRBLN and sRBLN efficiently delivered naringin to both hepatocytes and KCs in a balanced manner, reduced hepatocyte oxidative stress, and mitigated KC‐driven inflammation by polarizing KCs from the M 1 to M 2 phenotype. Such a pre‐treatment significantly alleviated drug‐induced liver damage and nearly restored the liver functions in the mouse model. This strategy introduces a novel paradigm for balanced liver cell‐targeted drug delivery with promising potential for ALF therapy.