Preparation and Characterization of Polysaccharide-Derived Smart Nanocarriers for Stimuli-Responsive Delivery of Natural Extracts in NSCLC Therapy

Non-small cell lung cancer (NSCLC) has a poor prognosis due to late diagnosis and high metastasis, while existing agents like Cucurbitaceae-derived Compound 1 are limited by low solubility, poor targeting, and high normal cell toxicity. This study aimed to construct a fluorinated hyaluronic acid nanocarrier (HA-2@1) to load Compound 1, improving its solubility/biocompatibility, enabling NSCLC-targeted delivery, and enhancing therapeutic efficacy. In vitro experiments included pH-responsive drug release testing, fluorescence spectroscopy for carrier-drug interactions, and CCK-8 cytotoxicity assays on A549 (NSCLC) and BEAS-2B (normal lung) cells, compared with free Compound 1. Results showed: HA-2@1 released 75% of Compound 1 at pH 5.0 (tumor microenvironment) vs. 43% at pH 7.4 (physiological condition) within 120 h; Compound 1 loading reduced HA-2 fluorescence by 26% (intermolecular quenching) with further aggregation-driven quenching at 100 μg/mL; HA-2@1 decreased A549 viability by 25% at 48 h, and its toxicity to BEAS-2B cells (7% at 200 μg/mL) was far lower than free Compound 1 (53%). In conclusion, HA-2@1 offers targeted delivery, fluorescence tracking, low toxicity, and efficient release, providing a promising nano-strategy for NSCLC therapy and a reference for natural product carrier optimization.