Codelivery of Doxorubicin and Carvacrol via a β-Cyclodextrin−Hyaluronic Acid Nanogel System for Targeted and Stimuli-Responsive Anticancer Therapy

Nanogel systems offer transformative potential in overcoming critical challenges of traditional therapies, such as poor solubility, low bioavailability, and systemic toxicity. In this study, nanogels were developed using thiolated hyaluronic acid (HASH) and vinyl sulfonated β-cyclodextrin (CDVS) via a water-in-oil emulsion method. The resulting HASH/CDVS nanogels uniquely integrate HA CD44-targeting capability with CD host-guest chemistry to encapsulate both hydrophilic doxorubicin hydrochloride (DOX) and hydrophobic carvacrol (CRV), enabling effective codelivery of chemically distinct drugs. The HASH/CDVS nanogels displayed a uniform spherical morphology with an average diameter of 200 ± 25 nm and a PDI of 0.21 ± 0.13. Stability studies confirmed structural integrity under physiological (150 mM PBS pH 7.4) and tumor-like (178 mM PBS pH 6.4 + 10 mM glutathione) conditions, with selective degradation triggered by hyaluronidase (150 U/mL), highlighting their enzyme-responsive behavior. <i>In vitro</i> release experiments demonstrated a sustained, stimuli-responsive release profile, with accelerated drug release in acidic and reductive environments mimicking the tumor microenvironment. Cellular uptake and cytotoxicity assays in triple-negative breast cancer cells confirmed efficient internalization and significantly enhanced therapeutic efficacy of the nanogel system. Overall, these HASH/CDVS-based nanogel represent the first nano dual-delivery system for DOX and CRV, offering a synergistic and tumor-responsive platform for advanced combination cancer therapy.