This study develops a magnetic hyperthermia-triggered siRNA delivery system based on PSMA targeting, achieving YY1 gene silencing and effective induction of ferroptosis in prostate cancer cells. The system integrates MRI imaging capabilities, providing a novel strategy for prostate cancer treatment.
Literature Overview
This article, published in the Journal of Experimental & Clinical Cancer Research, reviews the role of YY1 in prostate cancer drug resistance and summarizes its potential as a therapeutic target. It further analyzes the mechanism of YY1 silencing through magnetic hyperthermia-triggered siRNA delivery systems, which disrupt antioxidant systems and induce ferroptosis.
Background Knowledge
Prostate cancer (PCa) is one of the most common malignant tumors in males, with significantly increased treatment challenges in the metastatic castration-resistant prostate cancer (CRPC) stage. YY1, as a transcription factor, is overexpressed and closely associated with drug resistance, tumor metastasis, and poor prognosis in CRPC. Ferroptosis is an iron-dependent programmed cell death mechanism that can effectively kill drug-resistant tumor cells without affecting normal cells under specific metabolic stress conditions. This study employs a PSMA-targeted magnetic responsive nanocarrier to achieve YY1-specific silencing, while combining magnetic hyperthermia to trigger siRNA release and iron accumulation, thereby dual-inducing ferroptosis. Additionally, the system enables MRI imaging for real-time drug distribution monitoring, offering an innovative dual-response therapeutic platform with clinical translational potential for CRPC treatment.
Research Methods and Experiments
The study constructed a Glu-urea-Lys (GUL)-modified liposomal nanosystem (GUL@LsiYY1@MZ) targeting PSMA, encapsulating YY1 siRNA and Mn0.6Zn0.4Fe2O4 (MZ) nanoparticles. Under alternating magnetic field (AMF) stimulation, this system triggers siRNA release through YY1 silencing, downregulates SLC7A11 expression, disrupts glutathione metabolism, and induces lipid peroxide accumulation, ultimately causing ferroptosis in prostate cancer cells. Furthermore, the nanosystem provides MRI contrast enhancement capabilities for T2-weighted imaging.
Key Conclusions and Perspectives
Research Significance and Prospects
This study provides a PSMA-targeted, AMF-responsive gene silencing nanoplatform offering new insights for CRPC treatment. Future research will optimize in vivo delivery efficiency and explore applications in other ferroptosis-sensitive tumors to accelerate clinical translation.
Conclusion
By integrating YY1 silencing with ferroptosis mechanisms, this study developed a novel PSMA-targeted nanotherapeutic system. Through magnetic hyperthermia triggering, the system enables precise siRNA release while disrupting antioxidant defenses via the YY1-SLC7A11 pathway, inducing ferroptosis in prostate cancer cells. Experimental validation demonstrates excellent antitumor efficacy, MRI visualization capabilities, and biocompatibility in vivo. This provides effective tools for CRPC-targeted therapy and visualization, expanding new directions for ferroptosis applications in cancer treatment. Additionally, the study reinforces YY1 as a potential therapeutic target for tumor drug resistance, establishing a gene target for future RNA interference therapies. Results indicate that nanosystems combining targeted delivery with controlled release can achieve more efficient gene silencing and tumor cell killing while minimizing off-target effects, showing strong clinical translational potential.
