Design of a Multifunctional Nanozyme for Resolving the Proinflammatory Plaque Microenvironment and Attenuating Atherosclerosis.

Abstract

Persistent inflammation within atherosclerotic plaques is a crucial factor contributing to plaque vulnerability and rupture. It has become increasingly evident that the proinflammatory microenvironment of the plaque, characterized by heightened monocyte recruitment, oxidative stress, and impaired clearance of apoptotic cells, plays a significant role in perpetuating inflammation and impeding its resolution. Consequently, targeting and eliminating these proinflammatory features within the plaque microenvironment have emerged as a promising therapeutic approach to restore inflammation resolution and mitigate the progression of atherosclerosis. While recent advancements in nanotherapeutics have demonstrated promising results in targeting individual proinflammatory characteristics, the development of an effective therapeutic strategy capable of simultaneously addressing multiple proinflammatory features remains a challenge. In this study, we developed a multifunctional nanozyme based on Prussian blue, termed PBNZ@PP-Man, to simultaneously target and eliminate various proinflammatory factors within the plaque microenvironment. Through systematic investigations, we have elucidated the antiatherosclerotic mechanisms of PBNZ@PP-Man. Our results demonstrate that PBNZ@PP-Man possesses the ability to accumulate within atherosclerotic plaques and effectively eliminate multiple proinflammatory factors, leading to inflammation resolution. Specifically, PBNZ@PP-Man suppresses monocyte recruitment, scavenges reactive oxygen species, and enhances efferocytosis. Notably, PBNZ@PP-Man exhibits a much stronger efficacy to resolve the proinflammatory plaque microenvironment and attenuate atherosclerosis in comparison to the approach that merely eliminates one single risky factor in the plaque. It significantly enhances the inflammation resolution capabilities of macrophages and attenuates atherosclerosis. These results collectively underscore the importance of modulating the proinflammatory plaque microenvironment as a complementary strategy for resolving inflammation in atherosclerosis.