Multifunctional nanoparticles for immune regulation and oxidative stress alleviation in myocarditis

Abstract

Cardiac autoimmune injury and oxidative stress play critical roles in the development of myocarditis. Promising approaches for treating this condition include suppressing excessive immune responses and reducing oxidative stress in the myocardium. The programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) axis is known to regulate immune responses and prevent damage caused by T-cell overactivation, while elevated reactive oxygen species (ROS) contribute to the progression of myocarditis. In this study, we developed multifunctional nanoparticles (PMN@EDR) that overexpress PD-L1 and are loaded with edaravone (EDR). The PMN@EDR NPs were successfully synthesized and comprehensively characterized. PMN@EDR effectively targeted inflammation-stimulated CD4⁺ T cells and damaged myocardial cells, inhibiting CD4⁺ T-cell proliferation, activation, and the release of pro-inflammatory cytokines via the PD-1/PD-L1 pathway. Additionally, PMN@EDR further suppressed CD4⁺ T-cell activation and alleviated HL-1 cardiomyocyte damage by releasing EDR to eliminate free radicals. For the in vivo treatment of myocarditis, compared to traditional single-target anti-inflammatory and antioxidant drugs, PMN@EDR not only reduced inflammation and the release of inflammatory mediators but also decreased ROS levels, thereby minimizing cardiomyocyte apoptosis and improving cardiac function. In conclusion, the PMN@EDR-based modulation of immune responses and oxidative stress offers a promising therapeutic strategy for myocarditis.