<p>Background hepatocellular carcinoma (HCC) remains one of the most fatal malignancies, often resistant to conventional chemotherapy due to poor tumor selectivity, systemic toxicity, and rapid drug clearance. Plant-derived compounds offer safer alternatives, but their therapeutic potential is limited by low solubility, instability, and poor bioavailability. Objective this study aimed to overcome these limitations by developing a targeted nanocarrier system using chitosan nanoparticles (CSNPs) to encapsulate Capparis spinosa L. root extract (CRE), enhancing its stability, bioavailability, and site-specific delivery against HCC. Methods CSNPs were synthesized via ionic gelation and characterized for particle size, morphology, zeta potential, encapsulation efficiency, and in vitro release. Anticancer efficacy was evaluated using HepG2 cells (MTT and Annexin V/PI assays) and a thioacetamide-induced HCC rat model through biochemical and histopathological analyses. Results CSNPs/CRE exhibited sustained phytochemical release, optimal nanoscale size (~ 180 nm), and a positive surface charge conducive to hepatocellular uptake. In vitro, CSNPs/CRE significantly reduced HepG2 viability and induced apoptosis compared to free CRE or blank CSNPs (P &lt; 0.001). In vivo, CSNPs/CRE treatment markedly normalized liver function enzymes (AST, ALT, ALP, LDH, GGT), AFP, and bilirubin levels, while restoring serum albumin and total protein. Histopathology confirmed near-complete restoration of hepatic architecture. Conclusion by addressing the rapid degradation and poor solubility of CRE and enhancing tumor-targeted delivery, the CSNPs/CRE formulation offers a major advancement over conventional therapies. This smart nanocarrier system synergistically combines phytochemical potency with nano-enabled precision, presenting a promising and less invasive strategy for effective HCC management.</p> Graphical Abstract <p></p>