Here, we report novel cholinized-polymer functionalized lipid-based nanoparticles (CP-LNPs) for rapid and highly effective delivery of drugs to the liver, achieving targeting within 10 min and nearly 100% efficiency. In this study, CP-LNPs loaded with a promising antifibrotic agent curcumin (CP-LNPs/Cur) significantly improved the stability of curcumin under physiological conditions and its distribution in the liver. In vitro experiments demonstrated that CP-LNPs/Cur effectively suppressed the proliferation and migration of activated hepatic stellate cells (aHSCs), as evidenced by the decreased expression of α-SMA. Moreover, CP-LNPs/Cur attenuated oxidative stress levels in hepatocytes while improving mitochondrial physiological activity. In vivo antifibrosis studies have shown that CP-LNPs/Cur only require a low dose to significantly alleviate liver injury and collagen deposition, thereby preventing the progression of liver fibrosis. These findings indicated that CP-LNPs exhibit great potential in liver fibrosis therapy benefiting from the novel targeting strategy.