Engineering chitosan nanoparticles for targeted doxorubicin delivery in liver cancer: A mechanistic and preclinical review

Hepatocellular carcinoma (HCC) remains a major global health burden, characterized by poor prognosis, limited treatment options, and high chemoresistance. Doxorubicin (DOX), a widely used chemotherapeutic agent, exhibits potent antitumor activity but is constrained by systemic toxicity, rapid clearance, and multidrug resistance. In recent years, nanostructured chitosan-based delivery systems have emerged as a promising approach to overcome these challenges. Chitosan, a natural, biodegradable, and biocompatible polysaccharide, offers excellent chemical modifiability, mucoadhesive properties, and tumor-targeting potential, making it an ideal candidate for nanoparticle engineering. This review critically summarizes recent advancements in the design and application of chitosan-based nanocarriers for DOX delivery in liver cancer, with a focus on encapsulation strategies, surface functionalization, stimuli-responsive systems, and co-delivery platforms. Emphasis is placed on how chitosan modifications enhance drug stability, intracellular uptake, endosomal escape, and tumor-specific release while minimizing systemic toxicity. Finally, we summarize key translational challenges and future perspectives for advancing these promising nanocarriers toward clinical application.