Background <p>Rosuvastatin (RSV), which is a potent statin used for the treatment of hyperlipidemia, faces challenges in achieving targeted hepatic delivery due to limited solubility in water and extensive first pass metabolism. The overall goal of this study was to develop and optimize bovine serum albumin (BSA)-based nanoparticles for targeted hepatic delivery of RSV, leveraging their biocompatibility and liver-targeting potential.</p> Methods <p>RSV loaded BSA nanoparticles (RSV-BSA NPs) were prepared through a modified desolvation nanoprecipitation strategy, with formulation parameters optimized via a Box-Behnken design for the lowest possible particle size (PS) and polydispersity index (PDI) while the highest possible zeta (ZP) potential and encapsulation efficiency (EE%).</p> Results <p>The optimized formulation (F12) showed a particle size of 142.8 ± 3.5 nm, PDI of 0.198 ± 0.01, zeta potential of − 33.5 ± 1.1 mV, and EE% of 91.8 ± 1.4%. Transmission electron microscopy (TEM) images showed uniform, spherical nanoparticles with smooth surfaces. The in vitro release studies showed a controlled, biphasic release profile, with 84 ± 3.8% of RSV released over 24 h, as opposed to a rapid burst release from the free drug. Radiolabeling with technetium-99 m (⁹⁹ᵐTc) showed a radiochemical yield of 92.4 ± 1.3%, enabling biodistribution studies in Swiss albino mice. The ⁹⁹ᵐTc-RSV-BSA NPs showed significantly higher hepatic accumulation (25.5 ± 1.4%ID/g at 1 h) than the free drug solution (11.8 ± 0.8%ID/g and an extended retention time up to 24 h. In addition, pharmacokinetic studies further confirmed enhanced hepatic exposure (AUC₀–∞: 664.47%ID.h/g) and sustained liver retention for the nanoparticles.</p> Conclusion <p>Thus, RSV-BSA NPs have potential as a nanocarrier for targeted hepatic delivery of RSV with enhanced bioavailability and therapeutic efficacy in the treatment of liver problems.</p> Graphical Abstract <p></p>