摘要
Insufficient therapeutic response in cervical cancer is closely associated with enhanced redox buffering, mitochondrial metabolic adaptation, and drug damage repair, which collectively weaken the sustained cytotoxicity of conventional chemotherapy. Herein, we developed a poly(2-ethyl-2-oxazoline) (PEOz)-modified Cu 2+ /Ca 2+ -coordinated doxorubicin (DOX)-loaded nanoplatform, D/CCP-P, to integrate chemotherapy, oxidative stress remodeling, cuproptosis sensitization, and photothermal amplification. In this system, Cu/Ca-doped mesoporous polydopamine served as both a drug-loading scaffold and photothermal converter, while PEOz enabled weakly acidic charge-reversal to enhance tumor cell uptake. The Cu/Ca dual-ion design was designed to disrupt intracellular redox and mitochondrial homeostasis: Cu 2+ was associated with glutathione depletion and reactive oxygen species accumulation, whereas Ca 2+ was associated with mitochondrial perturbation and metabolic stress, thereby weakening cellular tolerance to therapeutic insults. D/CCP-P exhibited efficient DOX loading, with a drug loading content of 42.64%. The nanoplatform also showed favorable photothermal performance, with a photothermal conversion efficiency of 41.43%, and enabled stimuli-responsive DOX release under acidic, reductive, and near-infrared (NIR) irradiation conditions. Mechanistically, D/CCP-P increased ROS-associated stress and altered NDUFS8/HSP70 expression, while time-course and Cu-MPDA/CCP comparisons supported progressive, Cu/Ca-amplified cuproptosis-related changes; HUVECs retained relatively high viability under non-irradiated conditions. Overall, this cascade nanotherapeutic strategy may enhance DOX-mediated cervical cancer therapy through redox remodeling–cuproptosis sensitization–photothermal amplification. Download: Download high-res image (237KB) Download: Download full-size image
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