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

Abstract

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.