Spatiotemporal Circadian Oscillator Manipulation for Enhanced Ovarian Cancer Therapy Using a Versatile Nanoplatform

Circadian rhythm (CR) disruption has been confirmed as a contributing factor to tumor progression. However, regulating circadian genes shows an inhibitory effect on ovarian tumor initiation and progression, which highlights the urgent necessity to regulate tumors' CR to understand their role in ovarian cancer (OC) therapy precisely. Herein, a novel near-infrared (NIR) light-controlled spatiotemporal strategy is presented, aiming to manipulate ovarian tumors' CR while enhancing the efficacy of chemotherapy agents. To achieve this strategy, a versatile nanoplatform (NP^PEG-CS) that integrates the modified photothermal sensitizer IR-820 and a norcantharidin-platinum(IV) prodrug conjugate onto a cationic polyethylenimine (PEI) backbone coated with PEG-modified chondroitin sulfate (PEG-CS) for targeted delivery to ovarian tumors is designed. NP^PEG-CS effectively diminishes the CR amplitude upon NIR illumination, demonstrating its potential for innovative cancer treatment strategies. Additionally, molecular analyses reveal that this disruption involves calcium-mediated influx, triggered by the photothermal properties of NP^PEG-CS. When combined with chemotherapeutic agents, a disrupted clock can elevate tumor sensitivity to these drugs. This process effectively increases DNA-Pt adducts, reduces the activity of protein phosphatase 2A (PP2A), and promotes cell cycle arrest, synergistically amplifying DNA damage and inducing robust tumor apoptosis. The novel nanoparticle synergism offers innovative insights into harnessing CR as a therapeutic target for more effective cancer management.