Targeted delivery of gemcitabine to lung cancer cells via a hyaluronic acid-based nanoplatform

To mitigate the dose-limiting toxicity of gemcitabine (GEM) in lung cancer therapy, we developed a targeted hyaluronic acid (HA)-based nanoplatform with sustained drug-release capabilities—GEM@HA-(HAP/PSI). The system consisted of a hydroxyapatite/polysuccinimide (HAP/PSI) composite core for efficient drug loading, with surface-conjugated HA serving as a CD44-targeting ligand. Following systematic optimization using response surface methodology, the resulting spherical nanoparticles (∼100–200 nm) exhibited pH-responsive drug release, good biocompatibility, and negligible hemolytic activity. In vitro studies using CD44-high A549 and CD44-low H358 cells confirmed that CD44-mediated active endocytosis was the predominant uptake pathway for the nanoplatform. Treatment with the optimized formulation (GEM@HA-(HAP/PSI)10) led to significantly greater cytotoxicity, inhibition of cell migration and colony formation, and apoptosis induction than treatment with a non-targeted control formulation. Importantly, in A549 xenograft mouse models, GEM@HA-(HAP/PSI)10 achieved superior tumor growth suppression relative to free GEM while also maintaining a favorable safety profile. Collectively, these findings indicate that the HA-targeted nanoplatform developed in this study enhances the precision and therapeutic efficacy of GEM delivery and holds promise for reducing its systemic toxicity.