PSMA-targeted theranostic nanoplatform achieves spatiotemporally precise therapy and triggers ferroptosis in prostate cancer treatment

BACKGROUND: Ferroptosis, an iron-dependent form of regulated cell death, is crucial for the fate of tumors such as prostate cancer (PCa) under conditions of metabolic and oxidative stress. Consequently, the disruption of ferroptosis defense mechanisms could be lethal to these cancer cells, while sparing normal cells. Despite this potential, the development of effective and controlled in vivo therapies targeting ferroptosis remains underexplored. METHODS: In this study, liposomes modified with Glu-urea-Lys (GUL) encapsulating Mn0.6Zn0.4Fe2O4 (MZ) were employed as siRNA delivery vectors targeting Ying Yang 1 (YY1) for PCa treatment both in vitro and in vivo. The synergistic antitumor effects of the GUL@LsiYY1@MZ nanosystem were assessed using CCK8 assays, Western blot analysis, flow cytometry, and laser scanning confocal microscopy imaging in vitro. Additionally, the mechanisms underlying the ferroptosis effects were further explored through transcriptome and lipidomics sequencing. Intravenous administration was employed to treat subcutaneous tumors in a mouse model, and the tumor inhibitory effects, safety, and visibility on T2-weighted MRI were evaluated. RESULTS: The engineered GUL@LsiYY1@MZ nanosystem exploits the specific binding affinity of GUL for the prostate membrane-specific antigen (PSMA), facilitating targeted delivery and accumulation. Upon exposure to alternating magnetic fields (AMF), this system enables the precision-controlled release of siRNA into the cell, leading to the knockdown of YY1 expression. This downregulation subsequently affects the expression of the SLC7A11, thereby disrupting glutathione metabolism. Additionally, the introduction of excess Fe2+ induces iron overload, further promoting ferroptosis. Significantly, this therapeutic intervention restructured the metabolism of PCa cells, leading to a substantial intracellular accumulation of unsaturated fatty acids. This accumulation provided an abundant substrate for the generation of phospholipid peroxides, ultimately compromising plasma membrane integrity and inducing ferroptosis in PCa cells. Furthermore, the nanosystem also functions as a contrast agent, enhancing the T2-weighted MRI imaging of solid tumors. CONCLUSION: The GUL@LsiYY1@MZ nanosystem utilizes AMF-triggered release to downregulate SLC7A11, inducing ferroptosis and contributing to enhanced anti-tumor efficacy.