Tumor‐Specific Nano‐Herb Delivery System with High L‐Arginine Loading for Synergistic Chemo and Gas Therapy against Cervical Cancer

Abstract Cancer metastasis poses significant challenges in current clinical therapy. Osthole (OST) has demonstrated efficacy in treating cervical cancer and inhibiting metastasis. Despite these positive results, its limited solubility, poor oral absorption, low bioavailability, and photosensitivity hinder its clinical application. To address this limitation, a glutathione (GSH)‐responded nano‐herb delivery system (HA/MOS@OST&L‐Arg nanoparticles, HMOA NPs) is devised for the targeted delivery of OST with cascade‐activatable nitric oxide (NO) release. The HMOA NPs system is engineered utilizing enhanced permeability and retention (EPR) effects and active targeting mediated by hyaluronic acid (HA) binding to glycoprotein CD44. The cargoes, including OST and L‐Arginine (L‐Arg), are released rapidly due to the degradation of GSH‐responsive mesoporous organic silica (MOS). Then abundant reactive oxygen species (ROS) are produced from OST in the presence of high concentrations of NAD(P)H quinone oxidoreductase 1 (NQO1), resulting in the generation of NO and subsequently highly toxic peroxynitrite (ONOO − ) by catalyzing guanidine groups of L‐Arg. These ROS, NO, and ONOO − molecules have a direct impact on mitochondrial function by reducing mitochondrial membrane potential and inhibiting adenosine triphosphate (ATP) production, thereby promoting increased apoptosis and inhibiting metastasis. Overall, the results indicated that HMOA NPs has great potential as a promising alternative for the clinical treatment of cervical cancer.