Study on Echinacoside-Copper Metal-Phenolic Networks Hydrogel System Loaded with Diallyl Trisulfide for Local Treatment of Cervical Cancer.

Background/Objectives: Cervical cancer cells evade chemotherapy by upregulating antioxidant defenses (e.g., glutathione (GSH)). A platform that simultaneously amplifies ROS and suppresses antioxidant defense is a low toxicity strategy. This study presents a local nanoplatform that combines chemodynamic therapy (CDT) with chemotherapy for the localized treatment of cervical cancer. Methods: Diallyl trisulfide (DATS) was loaded into the echinacoside (ECH)-copper metal-phenolic networks (MPNs) nanoparticles (ECD NPs) through a one-step coordination assembly method. The nanoparticles were incorporated into a poloxamer/HPMC thermosensitive hydrogel for vaginal delivery. The formulation was characterized for size, drug loading, sol-gel transition, and pH-responsive release. Antitumor activity was evaluated in SiHa and HeLa cells via Cu2+ uptake, GSH depletion, ROS accumulation, apoptosis markers, and viability. In vivo efficacy and biosafety were assessed in an orthotopic cervical cancer model. Results: ECD NPs showed uniform size (~135 nm), high DATS loading (~27.6%). The ECD NPs-loaded hydrogel exhibited a sol-gel transition at 36.7 °C. The ECD NPs-loaded hydrogel released 16.4% of DATS at pH 7.4, 32.4% at pH 4.5, 64.8% at pH 6.5, and 80.9% at pH 5.6 over 24 h. Release was minimal at vaginal pH, clearly triggered at tumor pH, and fastest at lysosomal pH, confirming pH-responsive behavior. The ECD NPs-loaded hydrogel enhanced Cu2+ uptake, depleted GSH, elevated ROS, and reduced cell viability to <50% at 80 μg/mL. In the orthotopic model, the ECD NPs hydrogel achieved a tumor inhibition rate of 87.81%, significantly outperforming free DATS (65.3%) and blank MPN (55.62%) hydrogels, with no evident systemic toxicity. Conclusions: The ECD NPs hydrogel triggers a Cu2+-driven ROS/GSH cascade that combines copper-mediated oxidative stress with DATS-induced apoptosis for enhanced antitumor activity. Its vaginal localization, pH-responsive release, and biosafety profile support further evaluation for cervical cancer therapy.