CD11b-modified ROS/pH-responsive nanoparticles co-deliver Dioscin and siRNA to improve cardiac repair after myocardial infarction by reducing neutrophil recruitment

Myocardial infarction (MI) is a deadly disease that threatens global health. During pathogenesis, excessive oxidative stress and inflammatory responses may accelerate disease progression and cardiac dysfunction. However, the treatment with naturally active and gene-based drugs is limited by the complex microenvironment within the lesions. Therefore, this study aimed to construct a nanosystem co-delivering Dioscin (Dio) and small interfering RNA (siRNA) of intercellular adhesion molecule-1 (siICAM-1) to repair cardiac function after MI. Nanomaterials were also equipped with polydopamine (PDA) and CD11b to respond to reactive oxygen species/pH in the lesion environment and target neutrophils, respectively. As expected, Dio/siICAM-1@MSN@PDA-CD11b was successfully constructed to realize the rapid release of Dio and siICAM-1 under condition of pH6.4+H(2)O(2). It also exhibited enhanced targeting properties with more intracellular uptake by neutrophils. In vitro, after co-culture with nanoparticle-targeted neutrophil, damaged cardiomyocytes regained their proliferative capacity, accompanied by a decrease in the level of inflammatory cytokines and the repair of mitochondrial dysfunction. Pharmacokinetic evaluation revealed that Dio/siICAM-1@MSN@PDA-CD11b exhibited a markedly prolonged plasma clearance and extended blood circulation half-time. In vivo, Dio/siICAM-1@MSN@PDA-CD11b preferentially accumulated within the myocardial tissues of MI mice and co-localized with CD11b(+)Ly6G(+) neutrophils, thereby attenuating neutrophil recruitment, suppressing inflammatory responses, and ultimately improving cardiac function. More importantly, Dio/siICAM-1@MSN@PDA-CD11b exhibited excellent in vivo biosafety profiles. To conclude, Dio/siICAM-1@MSN@PDA-CD11b demonstrated the potential to improve cardiac function after MI by blocking neutrophil infiltration into damaged cardiomyocytes to alleviate the inflammatory response and avoid further disease progression. This co-delivery nanosystem therefore proposed a spatiotemporal paradigm for the treatment of MI, with prospects for clinical transformation.