Reactive Oxygen Species-Responsive Ferrocene Nanoparticles Delivering Small Interfering RNA Targeting NOP2/Sun RNA Methyltransferase Family Member 2 for Gastric Cancer Therapy

Silencing NOP2/Sun RNA methyltransferase family member 2 (NSUN2) effectively inhibits gastric cancer (GC) progression but is limited by RNase degradation, rapid renal clearance, and low uptake. Based on the characteristic high levels of reactive oxygen species (ROS) in the tumor microenvironment, this study designed and synthesized a novel ROS-responsive ferrocene nanoparticle loaded with siNSUN2 (PRPFc@siNSUN2). Under ROS conditions, the nanoparticle disintegrates to release siNSUN2. Characterization by proton nuclear magnetic resonance, transmission electron microscopy, dynamic light scattering, and ultraviolet–visible spectrophotometry revealed that PRPFc@siNSUN2 is spherical, with an average diameter of 88.79 ± 1.14 nm, an encapsulation efficiency of 83.10%, and a drug loading capacity of 13.85%. Moreover, these nanoparticles demonstrated excellent stability and, under hydrogen peroxide conditions, exhibited structural disruption leading to the release of siNSUN2, thereby confirming their high ROS responsiveness. In vitro, PRPFc@siNSUN2 markedly enhanced the inhibition of GC cell proliferation, migration, and invasion, and promoted apoptosis, accompanied by increased intracellular ROS and improved siNSUN2 uptake. In vivo studies further confirmed that PRPFc@siNSUN2 markedly enhanced the therapeutic efficacy of siNSUN2 against GC, while exhibiting low cytotoxicity and good biocompatibility. Overall, our findings indicate that PRPFc@siNSUN2, with its favorable morphology, stability, and ROS-triggered release, substantially improves the anti-GC effects of siNSUN2 by inhibiting GC cell proliferation, migration, and invasion, as well as by promoting apoptosis. These results support NSUN2 as a promising therapeutic target and underscore the potential of PRPFc@siNSUN2 nanoparticles in drug delivery, offering a novel strategy to improve clinical outcomes for GC patients.