Dual-target carboxymethylated mannan nanoparticles for enhanced pH-responsive monomethyl auristatin E delivery in hepatocellular carcinoma therapy

Hepatocellular carcinoma (HCC) is among the most prevalent and deadly cancers worldwide, with high recurrence and metastasis rates that significantly impact patient survival. Targeted therapy has emerged as a promising alternative to conventional treatments. This offers tumor-specific drug delivery while minimizing adverse systemic effects. In this study, we present folate acid (FA)-carboxymethylated mannan (CM)- monomethyl auristatin E (MMAE) conjugate (FA-CM-MMAE, FCMMM), an innovative glycosylated dual-target nanoparticle designed for the precise delivery of MMAE to HCC cells. These nanoparticles utilize FA and CM as their targeting ligands and exhibit pH-responsive drug release in acidic tumor microenvironments. This allows enhanced specificity and reduces off-target toxicity. In vitro studies have demonstrated that FCMMM nanoparticles selectively deliver MMAE to HepG2 cells via receptor-mediated pathways, alleviating MMAE-associated toxicity in normal cells. Furthermore, in vivo experiments in HCC-bearing mouse models have shown efficient tumor-specific accumulation of the drug, significant inhibition of tumor growth, and markedly lower levels of systemic toxicity than MMAE. This dual-targeting strategy integrates precise tissue targeting with controlled drug release. It addresses critical limitations of traditional HCC therapies such as nonspecific drug distribution, systemic toxicity, and drug resistance mechanisms. FCMMM shows potential as a next-generation nanoparticle platform for safer, more effective chemotherapeutic intervention in hepatic cancer.