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Background <p>Acute kidney injury (AKI) remains a major clinical challenge resulting from the intertwined processes of oxidative stress and macrophage-driven inflammation, both converging on mitochondrial dysfunction. We developed a glucosylated albumin nanoplatform (Glc<sup>6</sup>-AD<sup>11</sup>-Alb) designed to exploit glucose transporter 1-mediated uptake in inflammatory M1 macrophages while preserving the intrinsic antioxidant properties of albumin.</p> Results <p>Physicochemical characterization confirmed reproducible synthesis with defined degrees of functionalization and stable physicochemical properties. <i>In vitro</i>, Glc<sup>6</sup>-AD<sup>11</sup>-Alb demonstrated selective uptake in M1 macrophages and significantly reduced intracellular reactive oxygen species, validating its dual role in immune modulation and redox regulation. Positron emission tomography imaging with Cu-64 radiolabeling revealed preferential renal accumulation in ischemia–reperfusion injury (IRI) models, supporting macrophage-targeted delivery. <i>In vivo</i>, administration of Glc<sup>6</sup>-AD<sup>11</sup>-Alb attenuated renal dysfunction, suppressed pro-inflammatory and oxidative markers, and promoted tubular regeneration in pre- and post-treatment settings. Importantly, Glc<sup>6</sup>-AD<sup>11</sup>-Alb directly protected renal tubular epithelial cells by restoring mitochondrial membrane potential under oxidative and hypoxic stress. Seahorse metabolic flux analysis further confirmed enhanced oxidative phosphorylation, reduced glycolytic dependency, and improved coupling efficiency, indicating recovery of mitochondrial bioenergetics. Transmission electron microscopy demonstrated preservation of mitochondrial ultrastructure, including intact cristae and elongated morphology, consistent with improved ATP synthesis capacity.</p> Conclusions <p>Glc<sup>6</sup>-AD<sup>11</sup>-Alb acts through complementary mechanisms of macrophage-targeted immune modulation and mitochondrial protection, thereby disrupting the vicious cycle of inflammation and oxidative stress in AKI. This nanoplatform represents a clinically translatable therapeutic strategy with potential to improve outcomes in patients with ischemic kidney injury.</p>

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Optimization of M1 macrophage targeting using a glucosylated albumin nanoplatform for ROS scavenging and mitochondrial rescue in acute kidney injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月29日

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  • Ji Yong Park,
  • Jung Nam An,
  • Seong Min Lee,
  • Young Chan Ann,
  • Eunjin Bae,
  • Kyung Don Yoo,
  • Yong Chul Kim,
  • Hyeri Chae,
  • Joo Yeon Oh,
  • Ran Ji Yoo,
  • Dong Ki Kim,
  • Sung Hyun Hong,
  • Yon Su Kim,
  • Yun-Sang Lee,
  • Seung Hee Yang

摘要

Background

Acute kidney injury (AKI) remains a major clinical challenge resulting from the intertwined processes of oxidative stress and macrophage-driven inflammation, both converging on mitochondrial dysfunction. We developed a glucosylated albumin nanoplatform (Glc6-AD11-Alb) designed to exploit glucose transporter 1-mediated uptake in inflammatory M1 macrophages while preserving the intrinsic antioxidant properties of albumin.

Results

Physicochemical characterization confirmed reproducible synthesis with defined degrees of functionalization and stable physicochemical properties. In vitro, Glc6-AD11-Alb demonstrated selective uptake in M1 macrophages and significantly reduced intracellular reactive oxygen species, validating its dual role in immune modulation and redox regulation. Positron emission tomography imaging with Cu-64 radiolabeling revealed preferential renal accumulation in ischemia–reperfusion injury (IRI) models, supporting macrophage-targeted delivery. In vivo, administration of Glc6-AD11-Alb attenuated renal dysfunction, suppressed pro-inflammatory and oxidative markers, and promoted tubular regeneration in pre- and post-treatment settings. Importantly, Glc6-AD11-Alb directly protected renal tubular epithelial cells by restoring mitochondrial membrane potential under oxidative and hypoxic stress. Seahorse metabolic flux analysis further confirmed enhanced oxidative phosphorylation, reduced glycolytic dependency, and improved coupling efficiency, indicating recovery of mitochondrial bioenergetics. Transmission electron microscopy demonstrated preservation of mitochondrial ultrastructure, including intact cristae and elongated morphology, consistent with improved ATP synthesis capacity.

Conclusions

Glc6-AD11-Alb acts through complementary mechanisms of macrophage-targeted immune modulation and mitochondrial protection, thereby disrupting the vicious cycle of inflammation and oxidative stress in AKI. This nanoplatform represents a clinically translatable therapeutic strategy with potential to improve outcomes in patients with ischemic kidney injury.