Multifunctionally Modified Low Molecular Weight PEI for Efficient Gene Delivery and Ferroptosis-Induced Antitumor Activity

Efficient gene delivery coupled with tumor-specific cell death remains a key challenge in cancer gene therapy. Herein, we report a multifunctional cationic polymer (PFFc) that integrates gene delivery and ferroptosis induction. Low-molecular-weight PEI (600 Da) was used as a backbone and cross-linked with fluorinated and ferrocene-functionalized epoxides via ring-opening polymerization to yield fluorinated linker polymer (PF), ferrocene linker polymer (PFc), and their copolymer (PFFc). Fluorinated chains imparted hydrophobicity, self-assembly, and biocompatibility, while ROS-responsive thioacetal-ferrocene units served as an intracellular labile iron source, promoting Fenton reactions to induce ferroptosis. Structure-activity relationship studies showed that PFFc could achieve an optimal balance between the transfection efficiency and cytotoxicity. In proliferation assays, PFFc/p53 polyplexes exhibited strong gene-specific cytotoxicity, surpassing nontherapeutic controls (pGL-3) and even PF/p53 group, highlighting the critical role of p53. Mechanistically, PFFc/p53 simultaneously increased intracellular ROS via ferrocene-mediated Fenton reactions and suppressed the SLC7A11-GSH antioxidant axis, weakening antioxidant defenses and causing lipid peroxide accumulation, leading to efficient ferroptosis. Rescue experiments with ferroptosis inhibitors confirmed this mechanism. Overall, PFFc enables synergistic gene delivery and ferroptosis induction, achieving high transfection efficiency while precisely regulating programmed cell death, providing a promising platform for multifunctional antitumor nanomedicine.