Fabrication of Hyaluronic Acid‐Targeted Supramolecular Delivery Platform With pH and ROS‐Responsive Drug Release

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Abstract
A supramolecular drug delivery system is fabricated here based on the assembly of β‐cyclodextrin‐modified hyaluronic acid (HACD) and ferrocene (Fc) with pH‐sensitive polyhistidine (PHIS). The system demonstrates efficient encapsulation of hydrophobic anticancer drugs with high and stable drug loading capacity. The drug‐loaded nanoparticles utilize HACD as the hydrophilic corona, enabling active tumor targeting through CD44 receptor‐mediated endocytosis and exhibiting dual stimuli‐responsive release properties (ROS and pH). In the tumor microenvironment characterized by elevated ROS levels and acidic pH, the nanoparticles undergo structural disassembly, switching from controlled release to rapid drug liberation. Blank nanoparticles exhibit excellent biocompatibility, while drug‐loaded formulations demonstrate selective cytotoxicity with significantly reduced toxicity toward normal cells HFF‐1 and enhanced therapeutic efficacy against HeLa cancer cells. This nanoplatform significantly improves the aqueous solubility and biocompatibility of hydrophobic drugs, achieving intelligent delivery and double‐modal stimulus‐responsive release.

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