Tumor‐Responsive PLGA‐SS‐HA Nanoparticles for Zinc Complex Delivery Suppress Prostate Cancer via TR3/FTH1 Pathway

ABSTRACT Therapeutic resistance and redox imbalance remain major challenges in advanced prostate cancer, necessitating targeted delivery with pathway‐specific strategies. In the present work, we designed a tumor‐specific PLGA‐SS‐HA nanoparticle proposed for the controlled delivery of zinc complexes to modulate the TR3/FTH1 pathway. The amphiphilic conjugate forms nanoparticles of approximately 80 nm in diameter. The disulfide bond allows for the triggered delivery of Zn 2 + (80%–90% within 24 h) in the presence of glutathione under reductive conditions, while preventing premature release under physiological conditions. PLGA‐SS‐HA@Zn demonstrated enhanced anticancer efficacy compared with free ZnPPIX, reducing IC 50 values to 30–38 µg/mL in PC‐3 cells and 35–42 µg/mL in DU‐145 cells, whereas normal RWPE‐1 cells exhibited IC 50 values >70 µg/mL, indicating selective cytotoxicity. At a mechanistic level, there is clear evidence of a significant accumulation of ROS, loss of mitochondrial membrane potential, and apoptosis in more than 60% of the cells. At a molecular level, treatment induced ∼3‐fold upregulation of TR3 and Bax, suppression of FTH1 and Bcl‐2, and robust activation of cleaved caspase‐3 and PARP, confirming engagement of the intrinsic apoptotic pathway. Together, this redox‐sensitive nanoplatform enhances zinc‐mediated oxidative stress and selectively suppresses prostate cancer, providing a mechanistically defined therapeutic strategy.