ROS-responsive death receptor 5 fusion protein nano-delivery system enhances myocardial ischemia-reperfusion injury protection

The microenvironment characterized by inflammation and oxidative stress plays a crucial role in the pathogenesis of myocardial ischemia-reperfusion (I/R) injury. The death receptor 5 fusion protein (sDR5-Fc) specifically targets and blocks the key protein-tumor necrosis factor related apoptosis inducing ligand (TRAIL), which is involved in cell apoptosis. This study focuses on the development of reactive oxygen species (ROS) intelligent responsive sDR5-Fc nanoparticles, aimed at improving the pathological microenvironment associated with oxidative stress and inflammatory damage, inhibiting myocardial cell apoptosis while worsening, and enhancing the bioavailability and selectivity of sDR5-Fc. The successful synthesis of 6S-PLGE-PO-PEG was verified through infrared nuclear magnetic resonance and other analytical experiments. The ROS intelligent responsive sDR5-Fc nanoparticles (DPP) were successfully constructed <i>in vitro</i>, exhibiting a particle size of approximately 200 nm, as well as a certain stability and H₂O₂ responsive release ability. DPP demonstrated good biocompatibility. The cell viability and apoptosis assays indicated that DPP significantly reduced myocardial cell damage caused by hypoxia reoxygenation and decreased cell apoptosis. In myocardial I/R rat model, the administration of DPP nanoparticle displayed superior therapeutic effects compared to the sDR5-Fc group, evidenced by the reduction in myocardial infarction area, improvement in fibrosis, decreased myocardial cell apoptosis, increased cell proliferation, enhanced angiogenesis, and inhibition of myocardial hypertrophy. The synergistic effect of ROS responsive sDR5-Fc nanoparticles in mitigating I/R injury is expected to provide a new interdisciplinary treatment approach.