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NAD+ biosynthesis and mitochondrial repair in acute kidney injury via ultrasound-responsive thylakoid-integrating liposomes

Nature Biomedical Engineering volume 9, pages 1740–1757 (2025)Cite this article

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Abstract

Acute kidney injury (AKI) impairs the energy metabolism and antioxidant capacity of renal proximal tubular cells. Here we show that ultrasound-responsive liposomes integrating thylakoid fragments and encapsulating l-ascorbic acid can restore the energy supply and antioxidant capacity of the tubular cells as well as renal function in animal models of AKI. After intravenous injection, the liposomes preferentially accumulated in the injured kidneys and were internalized by proximal tubular cells. Quinolinate phosphoribosyltransferase expressed in thylakoid catalysed the biosynthesis of nicotinamide adenine dinucleotide (NAD+), prompting the recovery of damaged mitochondria. Local ultrasound stimulation activated electron transfer from ascorbic acid, which led to the cytoplasmic formation of NADH and to the restoration of adenosine triphosphate through the malate-aspartate shuttle. Concurrently, the enhanced pentose phosphate pathway facilitated NADPH biosynthesis and reduced the levels of reactive oxygen species. In mice and piglets with AKI, low doses of the liposomes prevented kidney damage.

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Fig. 1: AKI treatment using ultrasonic LipTk-AA.
Fig. 2: Characterization of LipTk-AA.
Fig. 3: Enhanced NAD+ synthesis and ATP production in PTCs by LipTk-AA.
Fig. 4: Efficient decrease of glycolysis and improvement of NADPH biosynthesis induced by LipTk-AA.
Fig. 5: Therapeutic efficacy of LipTk-AA in cisplatin-induced AKI mice.
Fig. 6: Effective in vivo inhibition of AKI–CKD transition.
Fig. 7: Treatment efficacy of LipTk-AA in AKI piglets.

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Data availability

The data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are available from the corresponding authors on reasonable request. Source data are provided with this paper.

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Acknowledgements

This work was supported by the National Science Fund for Distinguished Young Scholars (22025401) and the National Natural Science Foundation of China (22293034, 22293030, 32101140 and 22104005). We thank the Biological and Medical Engineering Core Facilities (Beijing Institute of Technology) for providing advanced equipment.

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Authors and Affiliations

  1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Chemical Biology Center, Peking University, Beijing, P. R. China

    Yao Lei, Wan-Ru Zhuang & Hai-Yan Xie

  2. School of Life Science, Beijing Institute of Technology, Beijing, P. R. China

    Yuzhu Wu, Helin Zhao & Weidong Nie

  3. School of Medical Technology, Beijing Institute of Technology, Beijing, P. R. China

    Guanghao Wu

  4. College of Chemistry, Nankai University, Tianjin, P. R. China

    Dai-Wen Pang

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  1. Yao Lei
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  2. Yuzhu Wu
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Contributions

H.-Y.X., Y.L. and D.-W.P. conceived the study, designed the experiments, performed the cellular and animal experiments and wrote the paper. Y.L., Y.W. and H.Z. performed the cellular and animal experiments and evaluated the anti-AKI activity in vivo. Y.L., W.-R.Z., W.N. and G.W. collected and analysed the data. H.-Y.X. provided financial support and directed the research. All authors discussed the results and commented on the paper.

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Correspondence to Dai-Wen Pang or Hai-Yan Xie.

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Extended data

Extended Data Fig. 1 Fluorescence imaging and corresponding quantitative analysis of mitochondrial membrane potential changes.

Mitochondria in PTCs were labelled with the potential sensor JC-1. Scale bar, 50 μm. Replicates are biological (n = 3) and all values are shown as the mean ± s.d. Significance calculated using a two-tailed t-test.

Source data

Extended Data Fig. 2 Representative imaging analysis of KIM-1+ tubules and proximal tubuli in renal tissue.

(a) Representative immunofluorescence staining of KIM-1+ tubules in renal tissue sections after 24 h different treatments. Higher-magnification images of the KIM-1+ tubules in renal tissue sections are shown at the bottom, and renal tubules were stained with anti-KIM-1 antibody and FITC-conjugated secondary antibody (green: KIM-1; blue: DAPI; wireframe indicates the magnified image). Scale bars, 500 μ (top) and 50 μm (bottom). (b) Representative fluorescence imaging (green: wheat germ agglutinin (WGA) lectin; blue: DAPI) and scanning electron microscopy (SEM) micrographs of proximal tubuli in mice after 24 h different treatments. The renal tubuli were labelled with FITC-conjugated-WGA lectin. Scale bars, 10 μm (top) and 5 μm (bottom).

Source data

Extended Data Fig. 3 Therapeutic efficacy of LipTk-AA in sepsis-induced AKI mice.

(a) Schematic diagram of the treatment schedule. (b) Representative immunofluorescence staining of KIM-1+ tubules (green: KIM-1; blue: DAPI) in renal sections after different treatments. Renal tubules were stained with anti-KIM-1 antibody and FITC-conjugated secondary antibody (green: KIM-1; blue: DAPI). Scale bar, 100 μm. (c) Representative images of PAS staining of different groups and corresponding tubule injury scores. Scale bar, 20 μm. (d) Representative immunofluorescence images and corresponding quantitative analysis of tubules with Ly6G+ neutrophils or CD68+ macrophages in kidney sections. Renal cells were stained separately with FITC conjugated-anti-CD68 antibody, anti-Ly6G+ antibody and FITC-conjugated secondary antibody. Scale bars, 20 μm. (e-f) Quantification of IL-1β and IL-6 levels in the serum of mice given different treatments. (g-h) Quantification of BUN and CRE levels in the serum of mice after different treatments. Replicates are biological (n = 5) and all values are shown as the mean ± s.d. Significance calculated using a two-tailed t-test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; ns, no significance.

Source data

Extended Data Fig. 4 Therapeutic efficacy of LipTk-AA in rhabdomyolysis (RM)-induced AKI mice.

(a) Schematic diagram of the treatment schedule. (b) Representative immunofluorescence staining of KIM-1+ tubules in renal tissue sections. Higher-magnification images of the KIM-1+ tubules in renal tissue sections are shown at the bottom, and renal tubules were stained with anti-KIM-1 antibody and FITC-conjugated secondary antibody (green: KIM-1; blue: DAPI; wireframe indicates the magnified image). Scale bars, 500 μm (top) and 50 μm (bottom). (c) Representative fluorescence imaging (green: wheat germ agglutinin (WGA) lectin; blue: DAPI) of renal proximal tubuli after 48 h different treatments. Scale bar, 10 μm. (d-e) Representative images of PAS staining of different groups and corresponding tubule injury scores. Scale bar, 40 μm. (f-g) Quantification of BUN and CRE levels in the serum of mice after different treatments for 24 h or 48 h. Replicates are biological (n = 5) and all values are shown as the mean ± s.d. Significance calculated using a two-tailed t-test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; ns, no significance.

Source data

Extended Data Fig. 5 Effective inhibition of AKI-CKD transition in repeated low doses of cisplatin induced nephrotoxic models.

(a) Illustration of the treatment schedule. (b) Representative images of PAS staining of renal sections from different groups. Scale bar, 20 μm. (c) Representative images of Masson trichrome staining on sagittal sections from different groups. Scale bar, 50 μm. (d) Representative fluorescence imaging of collagen I (Col-I) and (α-SMA) in kidneys of mice given different treatments. Renal tubules were stained with anti-α-SMA, Col-I antibody, and PE or FITC-conjugated secondary antibody. Scale bars, 50 μm. (e) Tubular injury score of the kidneys after different treatments. (f) Quantitative analysis of renal fibrosis in different groups, and (g-h) the mean fluorescence intensity (MFI) of collagen I (Col-I) and (α-SMA) in kidneys of mice given different treatments. Replicates are biological (n = 5) and all values are shown as the mean ± s.d. Significance calculated using a two-tailed t-test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; ns, no significance.

Source data

Extended Data Fig. 6 The assessment of system antigenicity in LipTk-AA&US-treated mice.

(a) Immunohistochemical analysis of CD3+ T cells and CD68+ macrophages in tissue sections. Scale bars, 20 μm. (b) Quantification of IL-6, IL-1β and TNF-α levels in the serum of mice after treated with LipTk-AA&US. Replicates are biological (n = 5) and all values are shown as the mean ± s.d.

Source data

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Source Data Figs. 2–7 and Extended Data Figs. 1–6

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Lei, Y., Wu, Y., Zhuang, WR. et al. NAD+ biosynthesis and mitochondrial repair in acute kidney injury via ultrasound-responsive thylakoid-integrating liposomes. Nat. Biomed. Eng 9, 1740–1757 (2025). https://doi.org/10.1038/s41551-025-01402-y

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