Doping-Engineered Pro-Angiogenic Nanozymes Orchestrate Ischemic Tissue Regeneration via Cytoprotection and Revascularization

Effective therapy for ischemic diseases requires not only timely restoration of perfusion but also protection of ischemic tissues from secondary insults, particularly oxidative-stress-induced injury. Here, we propose the concept of "proangiogenic nanozymes" and develop an efficient screening platform by doping angiogenic elements (Mg, Co, Cu, Zn, Sr, or Eu) into an archetypal antioxidative nanozyme, Prussian blue. Systematic assessment of catalytic activity and proangiogenic performance identified Cu-doped Prussian blue (CuPB) as the lead candidate. In addition to efficiently decomposing multiple reactive oxygen species, thereby attenuating oxidative stress, reducing apoptosis, and protecting ischemic tissues from secondary injury, CuPB nanozymes also stimulated angiogenesis, thereby accelerating tissue repair. In murine models of hind limb ischemia and myocardial infarction, CuPB conferred therapeutic benefits after both local and systemic administration, underscoring its translational potential. This proangiogenic nanozyme strategy offers an integrated and effective approach to ischemic tissue regeneration, bridging catalytic nanomedicine and vascular repair.