Fe-flavonoid nanozyme as dual modulator of oxidative stress and autophagy for acute kidney injury repair.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-07-28 eCollection Date: 2025-01-01 DOI:10.7150/thno.111874
Ranran Luo, Zhongsheng Xu, Chenxi Zhang, Zening Zhang, Pengchen Ren, Xiaojing He, Jingjing Zhang, Yun Liu
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引用次数: 0

Abstract

Background: Acute kidney injury (AKI), marked by a high mortality rate, remains a significant clinical challenge owing to limited therapeutic options. Oxidative stress is a key driver of AKI pathogenesis, underscoring the urgent need for innovative interventions. Recent advances demonstrate the potential of reshaping the oxidative stress microenvironment and activating intracellular autophagy to facilitate tissue repair. Nanotechnology-based antioxidants are emerging as promising approaches for AKI. Here, we present a novel nanoscale natural antioxidant platform for AKI treatment, incorporating reactive oxygen species (ROS) scavenging, oxidative stress modulation, anti-inflammatory properties and autophagy activation, which leverages these synergistic functions and lays the groundwork for clinical translation of next-generation nanotherapeutics in AKI. Methods: We synthesized a Fe-flavonoid nanozyme (FD@BSA) composed of ferric chloride hexahydrate, dihydromyricetin (DMY), and bovine serum albumin (BSA). FD@BSA integrated DMY's antioxidant and autophagy-activating functions with iron-mediated catalytic activity. Its therapeutic efficacy was evaluated in two oxidative stress-driven renal injury models: H2O2-induced ROS overload in human renal proximal tubular epithelial (HK-2) cells and glycerol-mediated AKI mice. Mechanistic studies employed laser confocal microscopy to visualize intracellular ROS scavenging and autophagy activation, while Western blotting and immunohistochemistry assessed protein expression and tissue-level pathology. Results: After intravenous administration, FD@BSA nanozyme selectively accumulated in the kidneys of water-restricted, glycerol-induced AKI mice. In vitro studies demonstrated that FD@BSA significantly decreased ROS accumulation in HK-2 cells, enhanced cell viability, attenuated inflammatory responses, and induced mitophagy, thereby preserving cellular homeostasis and alleviating injury. In vivo, FD@BSA treatment markedly ameliorated glycerol-induced AKI. Mechanistically, this protective effect was mediated by inhibition of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and upregulation of light chain 3 (LC3)-dependent autophagy, which together reduced ROS-driven cellular damage and mitigated renal injury, highlighting FD@BSA as a promising strategy for AKI. Conclusion: This study establishes FD@BSA nanozyme as a versatile nanotherapeutic platform for AKI, which can effectively remodel the oxidative stress microenvironment by scavenging excessive ROS and activating intracellular autophagy. Such multifunctionality extends FD@BSA's applicability beyond AKI to other ROS-driven pathologies, positioning it as a next-generation, nanotechnology-based strategy for the treatment of oxidative stress-related diseases.

铁类黄酮纳米酶在急性肾损伤修复中的氧化应激和自噬双重调节作用。
背景:急性肾损伤(AKI)以高死亡率为特征,由于治疗选择有限,仍然是一个重大的临床挑战。氧化应激是AKI发病机制的关键驱动因素,强调了创新干预措施的迫切需要。最近的进展表明,重塑氧化应激微环境和激活细胞内自噬以促进组织修复的潜力。基于纳米技术的抗氧化剂正在成为治疗AKI的有前途的方法。在这里,我们提出了一种新的纳米级天然抗氧化平台,用于AKI治疗,结合活性氧(ROS)清除,氧化应激调节,抗炎特性和自噬激活,利用这些协同功能,为下一代AKI纳米治疗药物的临床转化奠定了基础。方法:合成由六水氯化铁、二氢杨梅素(DMY)和牛血清白蛋白(BSA)组成的铁类黄酮纳米酶(FD@BSA)。FD@BSA将DMY的抗氧化和自噬激活功能与铁介导的催化活性结合起来。在两种氧化应激驱动的肾损伤模型中评估其治疗效果:h2o2诱导的人肾近端小管上皮细胞(HK-2) ROS超载和甘油介导的AKI小鼠。机制研究采用激光共聚焦显微镜观察细胞内ROS清除和自噬激活,而Western blotting和免疫组织化学评估蛋白质表达和组织水平病理。结果:静脉给药后,FD@BSA纳米酶选择性地在限水甘油诱导的AKI小鼠肾脏中积累。体外研究表明,FD@BSA可显著降低HK-2细胞中ROS的积累,增强细胞活力,减轻炎症反应,诱导有丝分裂,从而保持细胞稳态,减轻损伤。在体内,FD@BSA治疗可显著改善甘油诱导的AKI。从机制上讲,这种保护作用是通过抑制nod样受体家族pyrin结构域3 (NLRP3)炎症小体激活和轻链3 (LC3)依赖性自噬介导的,它们共同减少ros驱动的细胞损伤和减轻肾损伤,强调FD@BSA是AKI的一个有希望的策略。结论:本研究建立了FD@BSA纳米酶作为AKI的多功能纳米治疗平台,它可以通过清除过量的ROS和激活细胞内自噬来有效重塑氧化应激微环境。这种多功能性将FD@BSA的适用性从AKI扩展到其他ros驱动的病理,将其定位为下一代基于纳米技术的氧化应激相关疾病治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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