Dual-Targeted Galactose-TPP Dendrimers Modulate Mitochondrial Function and Downstream Outcomes in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains therapeutically challenging. Sorafenib, the standard first-line therapy for advanced HCC, suffers from poor aqueous solubility, non-specific biodistribution, dose-limiting toxicities, and the emergence of mitochondrial-mediated resistance. Here, we engineered a dual-targeted dendrimer nanoplatform that integrates hepatocyte-selective recognition with organelle-specific drug delivery. Galactose-functionalized Gal24 dendrimers were designed to engage the asialoglycoprotein receptor, while triphenylphosphonium enabled mitochondrial localization. Sorafenib was conjugated through CuAAC click chemistry to generate Gal24-TPP-Sora, which exhibited enhanced aqueous solubility, colloidal stability, and mitochondrial accumulation. In Hep3B cells, Gal24-TPP-Sora induced profound mitochondrial dysfunction, evidenced by elevated superoxide generation, ATP depletion, membrane depolarization, and enhanced apoptosis, accompanied by marked inhibition of proliferation, migration, and clonogenic survival. These effects surpassed free sorafenib and non-mitochondrial controls while preserving cytocompatibility and hemocompatibility. Collectively, this work establishes a precision nanotherapeutic strategy that couples receptor-mediated targeting with the mitochondrial intervention to potentiate sorafenib activity and overcome key therapeutic limitations in advanced HCC.