A tumor microenvironment responsive nanoplatform with oxidative stress amplification for effective MRI-based visual tumor ferroptosis

As a promising new form of non-apoptotic regulated cell death, ferroptosis has potential as an effective supplement to apoptosis-based cancer treatments. However, high intracellular glutathione (GSH) levels and insufficient hydrogen peroxide (H 2 O 2 ) in the tumor limit the efficacy of ferroptosis. Here, we designed a theranostic nanoplatform, named FCS/GCS, by incorporating amphiphilic polymer skeletal (P-SS-D), cinnamaldehyde prodrug (CA-OH) and iron ions (Fe 3+ )/gadolinium ions (Gd 3+ ) via chelation reactions between Fe 3+ /Gd 3+ and polyphenols. When delivered in the tumor microenvironment with high GSH level, the nanoparticles are depolymerized by the poly(disulfide) backbone of P-SS-D. The activated CA consumes the GSH and elevates intracellular H 2 O 2 , followed by a high level of Fenton reaction to generate abundant •OH levels. The generation of reactive oxygen species (ROS) further accelerates CA activation. The GSH consumption by disulfide , CA and Fe 3+ , downregulates GPX4 and generates •OH, which accelerate lipid peroxides (LPO) accumulation and consequently enhances ferroptosis. Additionally, the released Gd 3+ may serve as a contrast agent for tumor-specific T 1 -weighted magnetic resonance imaging (MRI). Thus, the rationally designed FCS/GCS system is a promising strategy for effective MRI-based visual ferroptosis therapy. Statement of significance Ferroptosis is a new form of non-apoptotic regulated cell death and has potential as an effective supplement to apoptosis-based cancer treatment. However, the efficiency of ferroptosis is limited by excessive glutathione level and insufficient hydrogen peroxide level in tumor site. In this study, we fabricate a theranostic nanoplatform (FCS/GCS) to amplify oxidation stress in tumor site for effective ferroptosis-based cancer treatment, and tumor specific magnetic resonance imaging is introduced for supervision. Our nanoplatform may provide a promising strategy for MRI-based visual ferroptosis therapy with high specificity and efficiency.