Purpose <p>To evaluate the preclinical efficacy and safety of transarterial chemoembolization (TACE) using doxorubicin-loaded biocompatible cellulose nanoparticles in a rabbit VX2 liver tumor model.</p> Materials and Methods <p>Following institutional animal care committee approval, 23 rabbits with VX2 liver tumors were randomized into three groups: Group A (<i>n</i> = 9) received doxorubicin-loaded cellulose nanoparticles with ethiodized oil; Group B (<i>n</i> = 9) received doxorubicin with ethiodized oil; and Group C (<i>n</i> = 5) served as untreated controls. Tumor size was monitored via ultrasound for 4&#xa0;weeks, and serum liver enzymes (aspartate transaminase and alanine transaminase) were measured on days 1, 3, and 7 to assess hepatotoxicity. An additional 10 healthy rabbits were randomized into two groups: Group D (<i>n</i> = 5) received doxorubicin-loaded cellulose nanoparticles with ethiodized oil, and Group E (<i>n</i> = 5) received doxorubicin with ethiodized oil, to measure serum doxorubicin concentrations up to 30&#xa0;min post-treatment.</p> Results <p>Group A demonstrated significantly slower overall tumor growth compared to Group C (<i>p</i> = 0.005) and slower growth between days 24 and 27 compared to Group B (<i>p</i> = 0.037). Pharmacokinetic analysis showed significantly lower serum doxorubicin levels in Group D than Group E at 2 and 5&#xa0;min post-delivery (<i>p</i> &lt; 0.05). Hepatotoxicity peaked at 24&#xa0;h, with significantly lower alanine transaminase levels in Group A compared to Group B (<i>p</i> = 0.025), normalizing by day 7.</p> Conclusion <p>TACE using doxorubicin-loaded cellulose nanoparticles demonstrated promising preclinical efficacy and safety compared to conventional TACE.</p> Level of Evidence <p>No level of evidence, Animal Study</p> Graphical Abstract <p></p>