CO delivery nanosystem based on regenerative bioactive zinc MOFs highlights intercellular crosstalk for enhanced vascular remodeling in CLI therapy

Therapeutic angiogenesis is a promising approach for the treatment of critical limb ischemia (CLI), but always face failure in clinical trials. The existing strategies primarily regulate a population of independent cells and ignore intercellular crosstalk, which may constrain efficacy. Inspired by the “self-healing” of organisms, we proposed a novel concept of “biomimetic dual cellular co-regulation”, i.e., regulating both vascular endothelial cells (VECs) or macrophages (Mφs), the protagonists in ischemic repair, and highlighting intercellular crosstalk to break the efficiency bottleneck of conventional strategies. Herein, bioactive zinc metal–organic frameworks (Zn-MOFs)-based carbon monoxide (CO) delivery nanoparticles coated with hyaluronic acid (HA)-CAG peptide (denoted as HA-CAG@ZIF8@CO) were developed, which can simultaneously target and regulate VECs and Mφs and enhance their interactions, with a view to amplify the synergistic cooperation in vascular remodeling. HA-CAG@ZIF8@CO promoted VECs morphogenesis through zinc ion and CO release, normalized microenvironment, and induced Mφ polarization to pro-healing M2-type, which further amplified angiogenesis through the secretion of pro-angiogenic cytokines. Excitingly, the intrinsic communication between VECs and M2-type Mφs enabled the significant enhancement of angiogenic activity. In summary, the dual cellular co-regulatory nanomedicine HA-CAG@ZIF8@CO modulates the intercellular crosstalk and represents a new possibility for therapeutic angiogenesis with clinical implications for ischemic repair.