Dong Qingrong, Shen Xiaomei, Fang Ge, Shi Jia, Zhu Xiafeng, Du Jiangfeng, Zhang Hui, Ge Cuicui
Department of Medical Imaging, First Hospital of Shanxi Medical University, Taiyuan, 030001, China.
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China.
Mater Today Bio. 2025 May 5;32:101839. doi: 10.1016/j.mtbio.2025.101839. eCollection 2025 Jun.
Diabetes mellitus (DM) induced wound healing impairment remains a serious health problem, which can lead to limb amputation and even shorten life span. Inhibiting ferroptosis of endothelial cells has shown promise in promoting tissue repair and regeneration. However, a majority of known ferroptosis inhibitors belong to either antioxidants or iron-chelators but with poor pharmacological adherence and even serious side effects. Herein, we construct a series of Prussian blue analogues-based nanozymes as ferroptosis nano-inhibitors to simultaneously achieve highly efficient intracellular iron capture and antioxidant properties. Through computational and experimental methods, the optimized Prussian blue analogues (MPBs) with highest iron chelating efficiency and efficacy (CuPBs) are screened out and both the CuPBs and the post-chelated products have been demonstrated to exhibit reactive oxygen species (ROS)-scavenging activities. As expected, the CuPBs successfully inhibit ferroptosis in high glucose-cultured skin repair cells, repairing their proliferation, migration and angiogenesis. Mechanistically, the CuPBs regulate ferroptosis by inhibiting iron accumulation and improving the antioxidant capacity of the Xc-GPX4 system. Moreover, in a murine diabetic wound model, the CuPBs remarkably promote the wound healing by inhibiting ferroptosis and increasing the M2/M1 macrophage ratio, showing a 2-fold higher wound closure rate than deferoxamine (DFO). Collectively, our study presents a general design strategy on developing ferroptosis nano-inhibitors and provides a promising approach for treating ferroptosis-related diseases.
糖尿病（DM）导致的伤口愈合受损仍然是一个严重的健康问题，可导致肢体截肢，甚至缩短寿命。抑制内皮细胞的铁死亡在促进组织修复和再生方面已显示出前景。然而，大多数已知的铁死亡抑制剂属于抗氧化剂或铁螯合剂，但药理依从性差，甚至有严重的副作用。在此，我们构建了一系列基于普鲁士蓝类似物的纳米酶作为铁死亡纳米抑制剂，以同时实现高效的细胞内铁捕获和抗氧化性能。通过计算和实验方法，筛选出具有最高铁螯合效率和功效的优化普鲁士蓝类似物（MPBs）（CuPBs），并且已证明CuPBs和后螯合产物均表现出活性氧（ROS）清除活性。正如预期的那样，CuPBs成功抑制了高糖培养的皮肤修复细胞中的铁死亡，修复了它们的增殖、迁移和血管生成。从机制上讲，CuPBs通过抑制铁积累和提高Xc-GPX4系统的抗氧化能力来调节铁死亡。此外，在小鼠糖尿病伤口模型中，CuPBs通过抑制铁死亡和增加M2/M1巨噬细胞比例显著促进伤口愈合，显示出比去铁胺（DFO）高2倍的伤口闭合率。总体而言，我们的研究提出了一种开发铁死亡纳米抑制剂的通用设计策略，并为治疗与铁死亡相关的疾病提供了一种有前景的方法。
