Redox-Responsive Multimodal Nanoplatform Based on Porous Silicon Nanoparticles with Copper Silicate Layer for Synergistic Anticancer Therapy.

Conventional cancer therapies have been limited by severe side effects and low treatment specificity, leading to reduced survival rates and a reduced quality of life. In particular, the heterogeneity of the reductive conditions, such as high glutathione (GSH) and HO levels and acquired drug resistance, remains a major obstacle that traditional drug delivery systems (DDS) struggle to overcome. While GSH is especially essential for maintaining cellular redox, its upregulation in cancers facilitates tumor survival and therapeutics, making it a pivotal target. Therefore, the development of multimodal therapeutic platforms capable of reductive condition-responsive activation, multimechanistic action, and selective cellular targeting is in high demand. In this study, we developed a redox-responsive multimodal nanoplatform (Cu-pSiDox-Glu) based on porous silicon nanoparticles (pSiNPs), which incorporate a copper(Cu)-silicate surface layer, the chemotherapeutic agent doxorubicin (Dox), and a glucosamine (Glu) moiety for tumor targeting. The system was designed to generate reactive oxygen species (ROS) under GSH/HO-rich conditions and to accumulate selectively in tumor cells via glucose transporter (GLUT)-mediated uptake. Cu-pSiDox-Glu showed enhanced copper-induced ROS generation via a Fenton-like reaction. Cellular analysis revealed selective uptake and potent cytotoxicity in Huh-7 hepatocellular carcinoma cells while maintaining low toxicity in normal HEK293 cells. These findings suggest that Cu-pSiDox-Glu is a promising multimodal nanoplatform for precise and effective cancer therapy through reductive condition-responsive ROS production and chemotherapeutic delivery.