Ubiquitination Flow Repressors: Enhancing Wound Healing of Infectious Diabetic Ulcers through Stabilization of Polyubiquitinated Hypoxia‐Inducible Factor‐1α by Theranostic Nitric Oxide Nanogenerators

Abstract

Current treatments for diabetic ulcers (DUs) remain unsatisfactory due to the risk of bacterial infection and impaired angiogenesis during the healing process. The increased degradation of polyubiquitinated hypoxia‐inducible factor‐1α (HIF‐1α) compromises wound healing efficacy. Therefore, the maintenance of HIF‐1α protein stability might help treat DU. Nitric oxide (NO) is an intrinsic biological messenger that functions as a ubiquitination flow repressor and antibacterial agent; however, its clinical application in DU treatment is hindered by the difficulty in controlling NO release. Here, an intelligent near‐infrared (NIR)‐triggered NO nanogenerator (SNP@MOF‐UCNP@ssPDA‐Cy7/IR786s, abbreviated as SNP@UCM) is presented. SNP@UCM represses ubiquitination‐mediated proteasomal degradation of HIF‐1α by inhibiting its interaction with E3 ubiquitin ligases under NIR irradiation. Increased HIF‐1α expression in endothelial cells by SNP@UCM enhances angiogenesis in wound sites, promoting vascular endothelial growth factor (VEGF) secretion and cell proliferation and migration. SNP@UCM also enables early detection of wound infections and ROS‐mediated killing of bacteria. The potential clinical utility of SNP@UCM is further demonstrated in infected full‐thickness DU model under NIR irradiation. SNP@UCM is the first reported HIF‐1α‐stabilizing advanced nanomaterial, and further materials engineering might offer a facile, mechanism‐based method for clinical DU management.

An Optimally Designed Engineering Exosome–Reductive COF Integrated Nanoagent for Synergistically Enhanced Diabetic Fester Wound Healing

“…VEGF secreted by vascular endothelial cells is a crucial factor that facilitates neovascularization following endothelial recruitment and regeneration. [ 55 ] It is generally recognized that HIF and VEGF expression are positively associated with each other. [ 56 ] Thus, we next sought to study the effects of hypoxia‐preconditioned exosomes treatments on the expression of HIF‐1α.…”

Two-dimensional nanovermiculite and polycaprolactone electrospun fibers composite scaffolds promoting diabetic wound healing

“…In addition, angiogenesis is crucial in the wound healing process, and previous investigations showed that poor vascularization contributed to diabetic wound healing delay. The proliferation, migration, and tube formation of endothelial cells are the main parts of the angiogenesis process [ 54 ]. In this study, the PCL/VMT composite scaffolds promoted L929 and MAEC cell adhesion and proliferation and promoted cell migration and tube formation in vitro.…”

Application of Metal–Organic Framework in Diagnosis and Treatment of Diabetes

“…Currently, NO is used as a gas drug for the treatment of diabetic wounds [ 213 , 215 , 216 ], but its clinical application in the treatment of diabetic ulcers (DU) has been hindered by the difficulty in controlling the release of NO. To solve this problem, Yiqi Yang et al proposed a smart near-infrared (NIR)-triggered NO nanogenerator (SNP@UCM) to precisely regulate the release of NO [ 153 ]. In this study, sodium nitroprusside (SNP) was used as the NO donor, and upconversion nanoparticles (UCNPs) were used as the core of the nanogenerator to convert the deep-tissue-penetrating near-infrared signal into visible light in situ ( Figure 9 ).…”

“…sO2: oxygen saturation. * p < 0.05, ** p < 0.01.Reproduced with permission [ 153 ]. Copyright 2021, Advanced materials .…”