Histidine as a Bridge: Fabricating pH-Sensitive and Target-Specific Hyaluronic Acid Nanoparticles via ZIF-8 for Drug Delivery

The self-assembly of hyaluronic acid (HA) into stable nanoassemblies remains a significant challenge. To address this, we report a novel strategy utilizing l-histidine (His) as a molecular bridge to integrate HA with a zeolitic imidazolate framework-8 (ZIF-8). The key to this approach is the covalent conjugation of His to the HA backbone, which enables Zn²⁺ from ZIF-8 to coordinate with the imidazole groups of His. This coordination facilitates the ZIF-8-induced assembly of HA into stable hybrid nanoparticles (HA-His/ZIF-8 NPs). The resulting system synergistically combines the CD44-targeting capability of HA with the pH-responsive dissociation of ZIF-8. These NPs demonstrated a high doxorubicin (DOX) loading capacity (0.34 mg/mg) and encapsulation efficiency (76.8%). Importantly, they exhibited controlled drug release with significant pH-dependency, achieving a cumulative release of 50.2% under weakly acidic conditions (pH 5.0) compared to only 12.4% at physiological pH (7.4). In vitro studies confirmed the target-specificity of the DOX-loaded HA-His/ZIF-8 NPs, which were efficiently internalized by CD44-positive MKN-45 gastric cancer cells via receptor-mediated endocytosis, leading to a potent cytotoxic effect (IC₅₀ = 1.71 μg•mL^-1). In contrast, the efficacy was significantly lower in CD44-negative SNU-216 cells (IC₅₀ = 5.22 μg•mL^-1). This work highlights the strategic use of His as a bridge to create a synergistic HA-ZIF-8 platform, offering a powerful and promising approach to the targeted therapy of CD44-overexpressing cancers.