Pharmacologically inherited carbon dots from <i>Salvia miltiorrhiza</i> with potent antioxidant activity and multi-pathway modulation for myocardial ischemia-reperfusion injury therapy

<b>Rationale:</b> Myocardial ischemia-reperfusion (I/R) injury remains a major clinical challenge that limits the efficacy of reperfusion therapy in acute myocardial infarction, mainly due to excessive production of reactive oxygen species (ROS) and the resulting oxidative stress, inflammation, and cardiomyocyte death. However, conventional antioxidant strategies show limited clinical efficacy, highlighting the urgent need for novel redox-regulating therapies. <b>Methods:</b> We synthesized carbon dot nanozymes (SM-CDs) via a green hydrothermal process using <i>Salvia miltiorrhiza</i>, a traditional Chinese medicinal herb. Their size, structure, and antioxidant enzymatic activities were thoroughly characterized. The contribution of surface functional groups to the superoxide dismutase (SOD)-like activity of SM-CDs were investigated by surface modification. <i>In vitro</i> antioxidant, anti-inflammatory, and anti-apoptotic effects were evaluated in RAW264.7 macrophages and H9C2 cardiomyocytes. <i>In vivo</i> therapeutic effects were accessed in a rat myocardial I/R model. Transcriptomics analysis was used to explore underlying cardioprotective mechanisms. Network pharmacology analysis was employed to study potential pharmacological activity inherited from the herbal precursor. <b>Results:</b> SM-CDs exhibit potent ROS-scavenging capacity, with surface carbonyl and hydroxyl groups playing key roles in their remarkable SOD-like activity. <i>In vitro</i>, SM-CDs effectively scavenged intracellular ROS, suppressed macrophage M1 polarization, and attenuated cardiomyocyte apoptosis. <i>In vivo</i>, intramyocardial injection of SM-CDs significantly reduced inflammation, apoptosis, and infarct size, while improving cardiac remodeling and functional recovery through fibrosis inhibition and enhanced neovascularization. These effects were potentially associated with inhibition of NF-κB and NOD-like receptor signaling pathways and activation of PI3K-Akt and FoxO pathways. Strong pathway concordance between SM-CD-regulated pathways and known therapeutic targets of <i>Salvia miltiorrhiza</i> suggests that SM-CDs may retain pharmacological activity from their herbal precursor. <b>Conclusions:</b> This study introduces SM-CDs as biocompatible nanozymes with potent antioxidant and cardioprotective potential for myocardial I/R injury.