ROS-responsive cationic polymer containing ferrocene for gene delivery and enhanced tumor cell apoptosis/ferroptosis

Abstract

The discovery of advanced materials capable of regulating cell death is crucial for the development of novel anti-cancer therapies. In this study, we designed a reactive oxygen species (ROS)-responsive cationic polymer, PFCA, to deliver the p53 gene, aiming to achieve synergistic apoptosis and ferroptosis by enhancing intracellular ROS and lipid peroxidation (LPO) levels. The polymer was constructed by covalently incorporating cinnamaldehyde (CA)and ferrocene (Fc) into its backbone via an ROS-responsive thioacetal linkage, which could be activated by endogenous ROS to trigger the release of CA. Once released, CA promoted ROS accumulation through GSH depletion, which led to the accelerated degradation of PFCA and sustained production of highly toxic •OH via the Fc-mediated Fenton reaction, thereby establishing an ROS self-amplification loop. Gene transfection assays showed that PFCA could efficiently deliver various types of genes with the transfection efficiency much higher than PEI. Furthermore, PFCA and p53 together downregulated intracellular GSH levels and upregulated ROS levels, resulting in the inactivation of GPX4 and the accumulation of LPO, which further potentiated apoptosis and ferroptosis in HeLa cells. This rationally designed ROS-responsive, self-amplifying polymeric gene delivery system provides an effective strategy for hybrid anticancer therapies and highlights the potential of oxidative stress-amplified modalities for therapeutic applications.