Redox-sensitive hyaluronic acid-based glycopeptide nanoparticles: Dual-action platform for mitochondrial disruption...

Conventional cancer treatments often suffer from poor tumor selectivity and systemic toxicity. This study introduces a hyaluronic acid (HA)-based glycopeptide polymer, HA-Cys-TK (HCTK), which leverages CD44-targeted delivery alongside glutathione (GSH)-responsive release. HCTK self-assembles into nanoparticles (88.43 ± 1.96 nm) with high conjugation efficiency. Its redox-sensitive linker enables the release of 80 % of peptides under tumor-mimicking conditions (10 mM GSH), compared to only 25 % in normal tissues. CD44-mediated targeting significantly enhances tumor uptake, yielding fluorescence levels 23.78 times higher in CD44-overexpressing B16 cells. In vitro, HCTK demonstrates potent cytotoxicity against B16 cells (IC₅₀ = 8.28 ± 0.48 μg/mL) with remarkable selectivity. Mechanistically, it targets mitochondria, causing membrane depolarization, ROS elevation, and caspase activation. In B16 tumor-bearing mice, HCTK achieves an 80.32 % tumor inhibition rate while exhibiting minimal systemic toxicity. By integrating targeted delivery with mitochondrial toxicity, HCTK offers a promising strategy for precision oncology.