Revascularization-driven nanozyme Therapy: Disrupting the vicious cycle of ROS and insufficient vascularization for chronic non-healing wound treatment.

Abstract

The pathophysiology of chronic non-healing wound is characterized by a deleterious interplay between impaired angiogenesis and excessive generation of reactive oxygen species (ROS), which perpetuates a vicious cycle exacerbated by persistent inflammation. Current therapeutic strategies lack efficacy in addressing this multifaceted pathophysiology. To dismantle this vicious cycle, we design a composite nanozyme (TCC) by encapsulating ultrasmall ceria nanoclusters (CeNC) and introducing tryptophan as competitive ligands within a biocompatible cobalt-based zeolitic imidazolate framework (Co-ZIF). The spatial confinement of Co-ZIF matrix effectively suppresses the aggregation of highly defective CeNC, while facilitating the internal Co-to-Ce electron transfer. Collectively, this synergistic effect increases Ce³⁺ fraction and modulates d-band center of CeNC, thereby enhancing its capability for catalytic decomposition of superoxide radicals. In vitro and in vivo investigations demonstrate that TCC exhibit exceptional ROS-scavenging capabilities. Concurrently, it effectively promotes angiogenesis via the released cobalt ions that stabilizing hypoxia-inducible factor-1α and further upregulating vascular endothelial growth factor expression. The dual functions of TCC synergistically disrupt the vicious pathogenic cycle of the malignant ROS accumulation and vascular insufficiency. Consequently, TCC significantly enhances pro-angiogenic outcomes in the wound microenvironment in vivo and in vitro. This work highlights a promising strategy of integrating nanozyme-based ROS-scavenging with vascular repair for comprehensive chronic non-healing wound management, offering translational potential for next-generation regenerative therapies targeting oxidative and vascular pathologies.