Organ‐Targeted Ionizable Lipid Nanoparticles Facilitate Sequence‐Activated Fluorogenic Probe for Precise Imaging of Inflammatory Liver Disease

Abstract Activatable near‐infrared (NIR) fluorogenic probes offer a potent tool for real‐time, in situ detection of hepatic biomarkers, significantly advancing the precision in diagnosing inflammatory liver disease (ILD). However, the limited distribution of small molecule fluorogenic probes in the liver and their rapid clearance impair the accuracy of fluorescence imaging and in ILD diagnosis. In this study, an effective utilization of ionizable lipid nanoparticles (iLNPs) is presented as liver‐targeted carriers for efficient delivery of fluorogenic probes, aiming to overcome biodistribution barriers and achieve accurate detection of hepatic biomarkers. Based on this strategy, a liver‐targeted NIR fluorogenic nanoprobe hCy‐H 2 O 2 @iLNP is prepared using hCy‐H 2 O 2 as a small molecule reporter for visualizing the over‐produced hydrogen peroxide (H 2 O 2 ) in situ of liver. Notably, iLNPs not only significantly enhance probe accumulation in the liver, but also enable sequence activation of fluorescent nanoprobes. This response is achieved through primary liposome‐dissociation release and secondary hCy‐H 2 O 2 response with pathological H 2 O 2 , enabling high‐precision detection of oxidative stress in hepatocytes. These distinctive features facilitate accurate early diagnosis of acetaminophen (APAP)‐induced inflammatory liver injury as well as lipopolysaccharide (LPS)‐induced hepatitis. Therefore, the organ‐targeted nanoprobe design strategy showcasts great potential for early and accurate diagnosis of lesions in situ in different organs.