L-Arginine-Loaded Gold Nanocages Mitigates Myocardial Ischemia/Reperfusion Injury by Promoting NO Production and Maintaining Mitochondrial Functions

Abstract Nitric oxide (NO) has the potential to ameliorate myocardial ischemia/reperfusion injury (MI/RI), and has emerging as key molecular for drug design. However, NO can be oxidized to more toxic peroxynitrite in the presence of reactive oxygen species (ROS), and cause secondary damage to cardiomyocytes. Herein, L-Arginine-loaded selenium-coated gold nanocages (AASP) were designed and synthesized. AASP after PCM modification achieved cardiomyocytes-targeted recognition, enhanced cellular uptake and photoacoustic imaging in vitro and in vivo, which significantly inhibited oxygen glucose deprivation/re-oxygenation (OGD/R)-induced H9C2 cells cytotoxicity and apoptosis. Mechanism investigation revealed that Nano-selenium firstly exhausted ROS, which prevented NO oxidation. L-arginine (Arg) loaded in gold nanocore was catalyzed by nitric oxide synthase (eNOS) to produce NO, which in turn blocked ROS release by regulating mitochondrial permeability transition pore (mPTP) closing, which maintained mitochondria functions, inhibited apoptosis. AASP administration in vivo effectively improved myocardial functions and vascular remodeling, inhibited myocardial apoptosis and fibrosis, and eventually attenuated MI/RI of rats. Transcriptomic analysis revealed that AASP relieved MI/RI of rats mainly by maintaining mitochondrial functions and regulating NO signal. Moreover, AASP showed good safety and biocompatibility in vivo. Taken together, our findings validated the rational design that L-Arginine-loaded selenium-gold nanocages ameliorated MI/RI of rats by promoting nitric oxide production and maintaining mitochondrial functions, which could be a more efficient way to treat MI/RI.