Copper nanoregulator with organelle-level precision reprograms COMMD1-Mediated copper homeostasis for myocardial...

Copper (Cu) homeostasis dysregulation is one of the key factor exacerbating mitochondrial dysfunction and impairing cardiac repair in myocardial infarction (MI). Herein, by integrating single-cell transcriptomics, clinical specimens, and animal models, we first identified COMMD1 as a key negative regulator of Cu homeostasis in MI. We then constructed a Cu nanoregulator, Qu@Cu-SS31, that selectively accumulate in the mitochondria of ischemic cardiomyocytes and release bioactive Cu²⁺ in a pH-responsive manner, enhancing mitochondrial function and promoting myocardial recovery. Mechanistic studies revealed that Qu@Cu-SS31 mediated significant downregulation of COMMD1, concomitant with downregulation of Cu transporters CTR1 and CCS. Additionally, Qu@Cu-SS31 showed robust reactive oxygen species scavenging ability. This COMMD1-Cu-ROS regulatory axis potently inhibited NLRP3-Caspase-1 dependent pyroptosis, and apoptosis via rebalance of Bcl-2/Bax expression. In a mice MI model, Qu@Cu-SS31 exhibited preferential accumulation in infarcted regions, leading to significant functional recovery, reduced infarct size, and enhanced tissue regeneration. Our work establishes a novel nanoregulator for Cu homeostasis restoration and illustrates the critical role of COMMD1 downregulation in mitigating mitochondrial damage, highlighting the therapeutic potential of Cu homeostasis regulation in cardiovascular applications.