Spermidine‐Based Carbon Quantum Dots Alleviate Liver Sinusoidal Endothelial Dysfunction by Inducing LSEC‐Derived NO to Ameliorate Hepatic Fibrosis and Portal Hypertension

ABSTRACT Portal hypertension (PHT), a life‐threatening complication of chronic liver disease, is driven by increased hepatic vascular resistance, with liver sinusoidal endothelial cell (LSEC) dysfunction and impaired nitric oxide (NO) signaling as key contributors. This study synthesized spermidine‐based carbon quantum dots (ST‐CQDs) and investigated their therapeutic effects on PHT. ST‐CQDs (average size 2.12 nm) exhibited good biocompatibility and effectively induced NO production in human immortalized LSECs (hiLSECs) by upregulating endothelial NO synthase (eNOS). In BDL and CCl 4 ‐induced PHT rat models, intravenous ST‐CQDs reduced portal pressure by decreasing intrahepatic vascular resistance, reversed LSEC capillarization, inhibited hepatic stellate cell activation and liver fibrosis, and alleviated liver inflammation—without altering systemic hemodynamics or causing organ toxicity. In vitro, ST‐CQDs reversed lipopolysaccharide‐induced LSEC dysfunction by restoring eNOS expression and NO release. These findings demonstrate ST‐CQDs as a potential therapeutic agent for PHT via targeting LSEC‐derived NO signaling.