Polyprodrug-siRNANanoparticles for ChemodynamicallyEnhanced Ferroptosis via Glutathione Peroxidase Downregulation

Ferroptosis has become an emerging paradigm in tumor therapy characterized by the accumulation of lipid peroxides (LPO). However, intracellular glutathione peroxidase 4 (GPX4) will lead to the clearance of LPO, weakening the therapeutic effect based on ferroptosis. Herein, the integration of the Fenton reaction amplifier and GPX4-targeted siRNA (si-GPX4) was proposed. A polyprodrug-siGPX4 nanoparticle (denoted as si-PDAFH NP) was prepared. On one hand, the si-PDAFH NP can respond to tumor microenvironment, leading to structural degradation of the NPs and release of therapeutic components. The released cinnamaldehyde and ferrocene can amplify the Fenton reaction to produce ^•OH, oxidizing unsaturated fatty acids to generate LPO. On the other hand, the expression of the GPX4 protein can be knocked down by si-GPX4, preventing the clearance of LPO. The results showed that the si-PDAFH NPs can significantly affect the tumor redox status related to ferroptosis and suppress tumor growth. Therefore, this study provides a new avenue to enhance ferroptosis for cancer treatment.