Inherently Therapeutic Plasmalogen-Based Nanoparticle Platform to Kill Ovarian Cancer Cells via Synergistic Ferroptosis Induction

Abstract

The standard treatment modality for high grade serous ovarian carcinoma (HGSOC), the most common and aggressive subtype of ovarian cancer, consists of surgery followed by chemotherapy, which is associated with major challenges including off-target effects and therapy resistance. Ferroptosis, a non-apoptotic regulated cell death program, has gained recent interest for its potential to effectively eliminate therapy-resistant cells. Leveraging ferroptosis, we report the development of an intrinsically therapeutic lipid-based nanoparticle platform through the incorporation of bioactive polyunsaturated fatty acid (PUFA)-containing vinyl ether-linked phospholipids, known as plasmalogens, into liposomes that encapsulate ferroptosis inducer RSL3 to effectively eliminate human OVCAR8 ovarian cancer cells. These bioactive lipids were chosen due to their ability to sensitize the cells toward ferroptosis, thus imparting on the nanocarriers a therapeutic role beyond their function as a delivery vehicle. The developed nanoparticle platform showed enhanced therapeutic efficacy compared to free RSL3 in OVCAR8 cells. In addition, by surface modification with hyaluronic acid (HA) through electrostatic layer-by-layer deposition, we further improved the therapeutic efficacy of the platform by increasing nanocarrier uptake in OVCAR8 cells. Further, we showed that the use of plasmalogen-containing nanocarriers for synergistic ferroptosis induction could be extended to nucleic acid cargo delivery via lipid nanoparticles (LNPs). Plasmalogen-containing LNPs that encapsulated small interfering RNA (siRNA) designed to downregulate expression of the gene responsible for ferroptotic evasion showed improved cancer cell cytotoxicity compared to the control LNPs without any plasmalogens. Overall, this integrated approach presents a novel strategy to tackle ovarian cancer, with the possibility of translation into an effective treatment approach for ovarian cancer patients who are not responsive to standard treatment modalities.