Nano-vitamin C and Iron-Loaded Polymeric Nanocarriers Cooperatively Amplify Oxidative Cancer Cell Death

Vitamin C exhibits potent pro-oxidant activity, yet its therapeutic translation is constrained by rapid systemic clearance, inefficient intracellular delivery, and the requirement for high therapeutic doses. Here, we developed a redox-active nanoplatform that overcomes these limitations by integrating ultrasmall nano-vitamin C with Fe(III)-loaded polymeric nanoparticles. Nano-vitamin C, generated via glyoxal-mediated molecular association, rapidly enters cells through energy-independent translocation, inducing an early cytosolic oxidative priming event characterized by reactive oxygen species (ROS) generation and glutathione depletion. Subsequent redox interaction between nano-vitamin C and Fe(III) promotes sustained Fenton chemistry, leading to amplified oxidative damage and lipid peroxidation. This combined oxidative response results in significantly enhanced cytotoxicity compared to either component alone and is associated with both ROS-mediated apoptotic signaling and iron-dependent ferroptosis-like features. Notably, the nano-vitamin C composite with Fe(III)-loaded polymeric nanoparticles efficiently penetrates and disrupts 3D tumor spheroids, inducing rapid spheroid collapse within days. Collectively, this work establishes a vitamin C-iron redox amplification strategy for enhancing oxidative cancer cell death and highlights a generalizable approach for developing redox-based nanotherapeutics.