Nanoparticle Endocytosis Mediated Intracellular Ion/Small Molecule Storm Triggered Mitochondrial Repair Determined Macrophage Reprogramming for Accelerate Diabetic Wound Healing

Abstract Eliminating reactive oxygen species (ROS) and inducing anti‐inflammatory M2 macrophages polarization are crucial for tissue repair. However, precisely regulating these processes in vivo is highly challenging. Despite small biomolecules and metal ions with ROS scavenging and M2 polarization potential, their high solubility hindered precise delivery, limiting therapeutic efficacy. This study proposes an innovative strategy involving the nanoscale and solidification of these molecules and ions to create pH‐responsive chlorogenic acid‐zinc nanoparticles. Leveraging macrophage's endocytosis and lysosomal acidity, these nanoparticles trigger precise metal ions and small molecules storm within 3 h after internalization, which effectively scavenges ROS and repairs damaged mitochondria. Additionally, it specifically inhibits the phosphorylation of NF‐κB p65 while activating the STAT6 signaling pathway within macrophages. This dual action reprograms macrophages toward the M2 phenotype, restoring immune homeostasis in the wound microenvironment. Notably, zinc ions probe is utilize to observe the dynamic process of the zinc ions storm and employed a series of mitochondrial‐related probes and transmission electron microscopy to validate the underlying mechanism of macrophage reprogramming through mitochondrial repair. The meticulously designed experiments on diabetic wound repair in mice fully validate these mechanisms, offering a universally applicable nanomedicine design approach for macrophage regulation and tissue repair.