An Injectable Multifunctional Nanosweeper Eliminates Cardiac Mitochondrial DNA to Reduce Inflammation.

Abstract

Myocarditis, a leading cause of sudden cardiac death and heart transplantation, poses significant treatment challenges. The study of clinical samples from myocarditis patients reveals a correlation between the pathogenesis of myocarditis and cardiomyocyte mitochondrial DNA (mtDNA). During inflammation, the concentration of mtDNA in cardiomyocytes increases. Hence, it is hypothesized that the combined clearance of mtDNA and its downstream STING pathway can treat myocarditis. However, clearing mtDNA is problematic. An innovative mtDNA scavenger is introduced, Nanosweeper (NS), which utilizes its nanostructure to facilitate the transport of NS-mtDNA co-assemblies for degradation, achieving mtDNA clearance. The fluorescent mtDNA probe on NS, bound to functional peptides, enhances the stability of NS. NS also exhibits robust stability in human plasma with a half-life of up to 10 hours. In a murine myocarditis model, NS serves as a drug delivery vehicle, targeting the delivery of the STING pathway inhibitor C-176 to the myocardium. This approach synergistically modulates the cGAS-STING axis with NS, effectively attenuating myocarditis- associated inflammatory cascade. This evaluation of NS in porcine models corroborated its superior biosafety profile and cardiac targeting capability. This strategic approach of targeted mtDNA clearance couple with STING pathway inhibition, significantly augments therapeutic efficacy against myocarditis, outperforming the conventional drug C-176, indicating its clinical potential.