Heart-targeted Amelioration of Sepsis-induced Myocardial Dysfunction by Microenvironment Responsive Nitric Oxide Nanogenerators in Situ

Abstract Background: Reduced levels of bioavailable nitric oxide (NO) plays a key role in maintaining cardiovascular homeostasis. However, it is clinically proven that the lack of spatial and temporal control of release restrict the application of NO.Destination: The purpose of this study is to design the heart-targeted and infection microenvironment-responsive NO-releasing biomaterials to efficiently ameliorate lipopolysaccharide (LPS)-induced cardiac dysfunction.Methods and Results: The heart-targeted NO delivery and in situ release system was synthesized using hollow mesoporous silica (MSN) as the carrier and L-arginine (LA) as the NO donor. PCM-MSN@LA was characterized by several analytical techniques. The directed myocardial delivery was successfully accomplished by primary cardiomyocyte-specific peptide (PCM) targeting and low-intensity focused ultrasound (LIFU) guidance. Upon the LIFU irradiation, although the concentrations of LA released from PCM-MSN@LA was low, the research exhibited high sensitivity to the increased nitric oxide synthase (NOS) activity in the infection microenvironment. Rapid targeting of the heart and in situ NO release enabled PCM-MSN@LA in combined with LIFU exerted extraordinary protective effects against LPS-challenged myocardial injury by reducing the recruitment of inflammatory cells, inhibiting oxidative stress and maintaining the mitochondria integrity. In particular, PCM-MSN@LA+LIFU relieved but not aggravated the circulation collapse in the infection environment.Conclusion: PCM-MSN@LA+LIFU exhibited significant cardioprotective effects against severe sepsis found in the hearts of the tested mice and reduced the side effects of NO diffusion. This technique could possibly be served as a new therapeutic method for sepsis-induced myocardial injury.