Hyaluronic Acid‐Modified Zeolitic Imidazolate Framework as a Drug Carrier for Aesculetin Delivery in Tumor‐Targeted Therapy

Efficient and tumor-targeted drug delivery systems can significantly enhance therapeutic efficacy while reducing adverse effects. Herein, a one-pot encapsulation method is employed to load the hydrophobic drug aesculetin (AE) into zeolitic imidazolate framework-8 (ZIF-8) nanocarriers (denoted as AE@ZIF-8), followed by surface modification with hyaluronic acid (HA) to construct the AE@ZIF-8/HA composite system. Due to the introduction of HA, the surface of AE@ZIF-8/HA carries a negative charge, which helps prolong its circulation time in the body and exhibits good blood compatibility and biological safety. Studies have shown that HA can specifically bind to the highly expressed CD44 receptor on the surface of tumor cells, promoting the selective enrichment of the drug at the tumor site. In the tumor microenvironment, HA can be degraded by hyaluronidase, while the ZIF-8 carrier decomposes under acidic conditions, enabling controlled release of AE. Compared with free AE, AE@ZIF-8/HA exhibits significantly enhanced antitumor activity both in vitro and in vivo. Therefore, this drug delivery system effectively addresses the poor water solubility and low bioavailability of free AE while achieving dual functions of tumor-targeting and stimuli-responsive drug release.