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<p>Acute kidney injury (AKI) is a rapid loss of renal function that has become a global health concern, with incidence rates reaching up to 50% in critically ill patients. Despite its growing prevalence, no effective pharmacological therapy for AKI currently exists, underscoring an urgent need for new treatments. Here, we present a drug repositioning approach in which the diabetes drug ertiprotafib is formulated within a supramolecular nanomedicine platform to enable biomarker-guided AKI therapy. Covalent modification of ertiprotafib with a multifunctional peptide drives the drug to spontaneously self-assemble into supramolecular nano-assemblies (SENs) via intermolecular interactions. In an ischemia–reperfusion AKI mouse model, these SEN nanoparticles preferentially accumulate in inflamed kidneys by penetrating the interstitium through disrupted tight junctions, a disease-induced structural biomarker. Subsequently, biomarker-guided enzymatic activation of the assemblies by the upregulated cathepsin B in injured tubular cells triggers the release of ertiprotafib, resulting in protein tyrosine phosphatase 1B (PTP1B) inhibition and modulation of the Src/ERK signaling pathway to suppress inflammatory responses and ameliorate disease progression. In contrast, healthy tubular cells and other organs (with low cathepsin B expression) experience minimal prodrug activation, which mitigates ertiprotafib’s off-target toxicity. Collectively, this coordinated supramolecular nanotherapy demonstrates an effective and safer strategy for AKI treatment by repurposing an existing drug.</p> Graphical Abstract <p></p>

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Repositioning of Ertiprotafib via supramolecular assembly enables biomarker-guided therapy for acute kidney injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月10日

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  • Hochung Jang,
  • Dongwon Shin,
  • Byeongmin Park,
  • Jae-Hyeon Lee,
  • Youngri Ryu,
  • Junha Lee,
  • Eunbyeol Ko,
  • Yoon Sook Ko,
  • Hee Young Lee,
  • Young Eun Choi,
  • Se Won Oh,
  • Sang-Kyung Jo,
  • Sangmine Lee,
  • Jooho Park,
  • Kwangmeyung Kim,
  • Sun Hwa Kim,
  • Myung-Gyu Kim,
  • Yoosoo Yang,
  • Man Kyu Shim

摘要

Acute kidney injury (AKI) is a rapid loss of renal function that has become a global health concern, with incidence rates reaching up to 50% in critically ill patients. Despite its growing prevalence, no effective pharmacological therapy for AKI currently exists, underscoring an urgent need for new treatments. Here, we present a drug repositioning approach in which the diabetes drug ertiprotafib is formulated within a supramolecular nanomedicine platform to enable biomarker-guided AKI therapy. Covalent modification of ertiprotafib with a multifunctional peptide drives the drug to spontaneously self-assemble into supramolecular nano-assemblies (SENs) via intermolecular interactions. In an ischemia–reperfusion AKI mouse model, these SEN nanoparticles preferentially accumulate in inflamed kidneys by penetrating the interstitium through disrupted tight junctions, a disease-induced structural biomarker. Subsequently, biomarker-guided enzymatic activation of the assemblies by the upregulated cathepsin B in injured tubular cells triggers the release of ertiprotafib, resulting in protein tyrosine phosphatase 1B (PTP1B) inhibition and modulation of the Src/ERK signaling pathway to suppress inflammatory responses and ameliorate disease progression. In contrast, healthy tubular cells and other organs (with low cathepsin B expression) experience minimal prodrug activation, which mitigates ertiprotafib’s off-target toxicity. Collectively, this coordinated supramolecular nanotherapy demonstrates an effective and safer strategy for AKI treatment by repurposing an existing drug.

Graphical Abstract