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-H2O2@iLNP　is　prepared　using　hCy-H2O2　as　a　small　molecule　reporter　for　visualizing　the　over-produced　hydrogen　peroxide　(H2O2)　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-H2O2　response　with　pathological　H2O2,　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.　©　2024　Wiley-VCH　GmbH.