Nanozyme-enhanced mitophagy to improve the efficacy of mesenchymal stem cells in myocardial infarction therapy

•This paper innovatively constructed PB@PEI@ICG nanozyme and used it to engineer MSCs for ROS scavenging to enhance the survival rate of MSCs in infarction zone.•We demonstrated that PB@PEI@ICG nanozyme could strengthen mitophagy in MSCs to further remove ROS that invaded the cells.•In this article, the fluorescent tracer ICG was loaded in Prussian blue nanozyme, and the nanozyme were used to track the distribution of stem cells in vivo.•Herein, we used pericardial injection for in vivo cell transplantation and found that PPI-MSCs stayed in the heart site for up to ten days. Mesenchymal stem cell therapy has emerged as a promising approach for the treatment of myocardial infarction. However, the challenge of low cell survival and retention post injection, particularly under the high levels of reactive oxygen species (ROS) and oxidative stress at the infarct site, has hindered their clinical application. Additionally, traditional drug delivery methods, such as intravenous injection, cannot meet the demand for long-term stem cell residence at the infarct site, which is another critical issue that impedes the therapeutic efficacy of stem cells. Herein, we synthesized indocyanine green-enriched Prussian blue nanozyme, called PB@PEI@ICG, which not only possessed remarkable ROS scavenging capability but also exhibited superior fluorescent tracer property. Subsequently, we engineered mesenchymal stem cells (MSCs) with PB@PEI@ICG by co-culture and found that the introduction of the nanozyme significantly enhanced mitophagy by BNIP3 and PINK1 pathways, which in turn promoted ROS scavenging and protected MSCs from cell death induced by the harsh infarct microenvironment. Furthermore, we employed pericardial injection as an alternative delivery method to prolong the residence time of MSCs at the infarct site, enabling real-time tracking via the fluorescence property of the nanozymes. The results demonstrated that PB@PEI@ICG nanozyme could significantly improve the survival and retention of MSCs at the infarct site, thereby enhancing the therapeutic effect for myocardial infarction. In conclusion, this study presents a novel strategy for stem cell therapy in myocardial infarction by using mitophagy-enhancing nanozyme to scavenge ROS for enhancing the therapeutic potential of stem cells. PB@PEI@ICG (PPI) nanozyme-engineered mesenchymal stem cells (MSCs) enhance mitophagy to eliminate ROS and boost cellular vitality. Furthermore, pericardial injection could prolong the