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Oral mitochondrial transplantation using nanomotors to treat ischaemic heart disease

Nature Nanotechnology volume 19, pages 1375–1385 (2024)Cite this article

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A Publisher Correction to this article was published on 23 July 2024

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Abstract

Mitochondrial transplantation is an important therapeutic strategy for restoring energy supply in patients with ischaemic heart disease (IHD); however, it is limited by the invasiveness of the transplantation method and loss of mitochondrial activity. Here we report successful mitochondrial transplantation by oral administration for IHD therapy. A nitric-oxide-releasing nanomotor is modified on the mitochondria surface to obtain nanomotorized mitochondria with chemotactic targeting ability towards damaged heart tissue due to nanomotor action. The nanomotorized mitochondria are packaged in enteric capsules to protect them from gastric acid erosion. After oral delivery the mitochondria are released in the intestine, where they are quickly absorbed by intestinal cells and secreted into the bloodstream, allowing delivery to the damaged heart tissue. The regulation of disease microenvironment by the nanomotorized mitochondria can not only achieve rapid uptake and high retention of mitochondria by damaged cardiomyocytes but also maintains high activity of the transplanted mitochondria. Furthermore, results from animal models of IHD indicate that the accumulated nanomotorized mitochondria in the damaged heart tissue can regulate cardiac metabolism at the transcriptional level, thus preventing IHD progression. This strategy has the potential to change the therapeutic strategy used to treat IHD.

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Fig. 1: Schematic illustrations and characterization of CM/NM/Mito and the workflow of the oral delivery system CM/NM/Mito@Cap.
Fig. 2: Cellular uptake, selective exocytosis and therapeutic effects of CM/NM/Mito.
Fig. 3: Characterization of CM/NM/Mito crossing multiple physiological barriers and targeting the ischaemic heart.
Fig. 4: In vivo therapeutic efficacy of CM/NM/Mito@Cap on IHD.
Fig. 5: Cardiac multi-omics analysis of the CM/NM/Mito@Cap effect on acute IHD.
Fig. 6: Cardiac transcriptomics analysis of the CM/NM/Mito@Cap effect on chronic IHD.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. There are no data from third-party or publicly available datasets. RNA sequencing data are deposited in NCBI’s Sequence Read Archive (SRA) and are accessible through accession numbers PRJNA1089164 and PRJNA1089186. Raw data of non-targeted metabolomics analysis are deposited in MetaboLights and are accessible through accession number MTBLS9785. All data generated as part of this study are available from the corresponding author upon reasonable request. Source data for Figs. 1–5 are available in separate source data files for Figs. 1f–i, 2d,f,h–k,m, 3f–h,j,l, 4c,e,g,i–k and 5g–i, respectively. Source data for Extended Data Figs. 1–6 are available in separate source data files for Extended Data Figs. 1b,c, 2c,d–g, 3c,e,g,h, 4a,d,e and 5b,c,e–h; Extended Data Fig. 6a, b, d. Source data are provided with this paper.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (22175096 (C.M.), 22275095 (M.W.), 82272098 (M.Z.)), the Priority Academic Program Development of Jiangsu Higher Education Institution, Jiangsu Key Laboratory of Biofunctional Materials and Jiangsu Collaborative Innovation Center of Biomedical Functional Materials. We thank L. Bianji for editing the English text of a draft of this manuscript.

Author information

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  1. These authors contributed equally: Ziyu Wu, Lin Chen.

Authors and Affiliations

  1. National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China

    Ziyu Wu, Lin Chen, Wenyan Guo, Jian Shen, Chun Mao & Mimi Wan

  2. Department of Vascular Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China

    Ziyu Wu, Wentao Jiang & Min Zhou

  3. Department of Vascular Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, China

    Jun Wang, Haiya Ni, Jianing Liu & Min Zhou

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Contributions

J.S., C.M., M.Z. and M.W. conceived and designed the project. Z.W. and L.C. prepared the samples and conducted most of the measurements. W.G. helped with the synthesis of materials. W.J. performed the assessment of chemotactic behaviour. H.N., J.W. and J.L. assisted in animal experiments. Z.W. and M.W. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Chun Mao, Min Zhou or Mimi Wan.

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Nature Nanotechnology thanks Huile Gao, Catherine Gorick and Gokhan Burcin Kubat for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Isolation and nanomotorization of mitochondria.

a. CLSM images of MitoTracker Deep Red labelled huMSCs and their mitochondria before and after isolation (scale bar: 20 μm). b and c. The hydrated diameter and zeta potential of mitochondria, NM/Mito and CM/NM/Mito. Data are presented as means ± SD (n = 3 biologically independent samples). d. Synthesis process of M-Arg, the basic unit of NM. e. 1H NMR of M-Arg in D2O. f. Synthesis process of the diselenide cross-linker. g. 1H NMR of diselenide cross-linker in DMSO-d6. h. Possible synthesis process of NM/Mito. i. CLSM images of NM/Mito. (NM was labelled with FITC, and mitochondria was labelled with MitoTracker Deep Red, scale bar: 10 μm). j. Coomassie brilliant blue staining of mitochondria and NM/Mito after SDS–PAGE.

Source data

Extended Data Fig. 2 Construction and characterization of CM/NM/Mito.

a. Synthesis process of CM/NM/Mito. b. Fluorescence images of WGA-labelled H9c2 cells and CM before and after lysis (scale bar: 100 μm). c. Western blotting of cardiomyocyte membrane markers. Cx43: connexin-43, Na/K ATPase: sodium-potassium ATPase. d and e. Quantitative analysis of unmodified mitochondria and NM/Mito after staining with JC-1, using antimycin A-treated unmodified mitochondria and NM/Mito as the control (n = 6 biologically independent samples). f and g. Mitochondrial complexes I (f) and V (g) analysis of unmodified mitochondria, NM/Mito and CM/NM/Mito (n = 4 biologically independent samples). h. Flow cytometric analysis of cellular NO levels of normal and damaged H9c2 cells after incubation with CM/NM/Mito for 24 h. The gating strategies were corresponded to Fig. 1h and i. Data were presented as means ± SD. Statistical significance was calculated via two-tailed unpaired Student’s t test in d, e, and one-way ANOVA with two-tailed LSD multiple comparisons test in f, g. Source data for c is provided as a Source Data file.

Source data

Extended Data Fig. 3 Chemotaxis behaviour of CM/NM/Mito.

a. Schematic illustration of the Y channel. b-e. Fluorescence images (120 min) and corresponding quantitative analysis of the normalized fluorescence intensity in reservoir ii and iii at different time after addition of CM/NM/Mito (b and c) and unmodified mitochondria (d and e) (scale bar: 500 μm; n = 3 biologically independent samples). f. Schematic illustration of the Ψ microfluidic device. g. Fluorescence images and corresponding fluorescence intensity distribution of CM/NM/Mito and unmodified mitochondria in the microfluidic device applying gradient concentrations of damaged H9c2 cell lysate and normal H9c2 cell lysate (scale bar: 500 μm). h. Fluorescence images and fluorescence intensity distribution of CM/NM/Mito and unmodified mitochondria in the microfluidic device applying gradient concentrations of normal H9c2 cell lysate (scale bar: 500 μm). Data are presented as means ± SD. Statistical significance was calculated via two-tailed unpaired Student’s t test in c, e.

Source data

Extended Data Fig. 4 Characterization of GJCs formation, membrane fusion and mitochondrial morphology.

a. Calcein AM-stained IEC-6 cells and H9c2 cells were incubated with unmodified mitochondria, NM/Mito, CM/NM/Mito, and CM/NM/Mito + CBX for 30 min, and the fluorescence changes in the supernatants were quantitatively analysed (i: control; ii: unmodified mitochondria; iii: NM/Mito; iv: CM/NM/Mito; v: CM/NM/Mito + CBX; n = 3 biologically independent cell samples). b. CLSM images of normal IEC-6 cells and damaged H9c2 cells co-incubated with CM/NM/Mito for 6 h (MitoTracker: NM/Mito component; WGA: CM component; DiL: IEC-6 or H9c2 cell membranes; Hoechst 33342: nuclei; scale bar: 20 μm). c and d. CLSM images (c) and mitochondrial morphology analysis (d) of H9c2 cells after co-incubation with different samples for 24 h and stained by MitoTracker (MitoTracker: mitochondria, Hoechst 33342: nuclei; scale bar: 20 μm; n = 20 cells examined over two independent experiments). e. Intracellular ATP levels of H9c2 cells co-incubated with different samples (n = 4 biologically independent cell samples). Samples in c-e: i, normal; ii, control; iii, unmodified mitochondria; iv, NM/Mito; v, CM/NM/Mito. Data were presented as means ± SD. Statistical significance was calculated via one-way ANOVA with two-tailed LSD multiple comparisons test in a, d, e.

Source data

Extended Data Fig. 5 Characterization of pH responsiveness, pharmacokinetics and cardioc delivery efficiency of CM/NM/Mito@Cap.

a. Disintegration process of large-sized enteric capsules with fuel in PBS with different pH values. b. Curve of fluorescence intensity in the lower chamber after adding Mitotracker-labelled CM/NM/Mito or unmodified mitochondira to the upper chamber in the transwell-based intestinal epithelial barrier model. Data were presented as means ± SD (n = 3 biologically independent cell samples). c. Curve of fluorescence intensity in serum at different times after administration of Mito@Cap and CM/NM/Mito@Cap in rats (n = 3 biologically independent animal samples). d-f. Ex vivo imaging of hearts (d) and cardiac delivery efficiency of Mito@Cap, NM/Mito@Cap and CM/NM/Mito@Cap at different time after oral administration of in acute IHD rats (e) and chronic IHD rats (f) (n = 4 biologically independent animal samples). g. Ex vivo imaging of hearts and cardiac delivery efficiency of CM/NM/Mito@Cap (third in die, tid) and CM/NM/Mito@Cap (quaque die, qd) at 24 h after oral administration of in chronic IHD rats (n = 5 biologically independent animal samples). h. CLSM images and quantification of fluorescence intensity of cardiac sections at 6 h after oral administration of CM/NM/Mito@Cap in acute IHD rats (i: proximal; ii: middle; iii: distal; MitoTracker: CM/NM/Mito; DAPI: nuclei; scale bar: 100 μm; n = 3 biologically independent animal samples). Data were presented as means ± SD. Statistical significance was calculated via two-tailed unpaired Student’s t test in g and one-way ANOVA with two-tailed LSD multiple comparisons test in h.

Source data

Extended Data Fig. 6 In vivo biocompatibility of CM/NM/Mito at the end of treatment in the chronic IHD model.

a and b. Blood routine (a) and blood biochemical analysis (b) (n = 4 biologically independent animal samples). c and d. H&E (c) and myeloperoxidase (MPO)-immunohistochemical stained main organs and corresponding quantitative analysis (d) (scale bar: 200 μm; n = 4 biologically independent animal samples). e. H&E stained ileum of rats (scale bar: 200 μm). Data were presented as means ± SD.

Source data

Extended Data Fig. 7 Transcriptomics analysis in the acute and chronic IHD model.

a. Venn diagram for the DEGs detected in hearts after oral administration of CM/NM/Mito@Cap in the acute IHD model (n = 3 biologically independent animal samples in the sham group; n = 4 biologically independent animal samples in the control group and oral administration of CM/NM/Mito@Cap group). b. Venn diagram for the DEGs detected in hearts after oral and intravenous administration of CM/NM/Mito@Cap and CM/NM/Mito in the chronic IHD model (n = 3 biologically independent animal samples in per group). The P values were determined using the negative binomial distribution, and then the Benjamini–Hochberg procedure was used for multiple hypothesis testing correction.

Extended Data Table 1 Studies on Mitochondrial Transplantation for IHD
Full size table

Supplementary information

Supplementary Information

Supplementary Discussion, Figs. 1–17 and Table 1.

Reporting Summary

Supplementary Data 1

Statistical source data for Supplementary Fig. 6.

Supplementary Data 2

Statistical source data for Supplementary Fig. 8.

Supplementary Data 3

Statistical source data for Supplementary Fig. 10.

Supplementary Data 4

Statistical source data for Supplementary Fig. 17.

Source data

Source Data Fig. 1

Statistical source data for Fig. 1f–i.

Source Data Fig. 2

Statistical source data for Fig. 2d,f,h–k,m.

Source Data Fig. 3

Statistical source data for Fig. 3f–h,j,l.

Source Data Fig. 4

Statistical source data for Fig. 4c,e,g,i–k.

Source Data Fig. 5

Statistical source data for Fig. 5g–i.

Source Data Extended Data Fig. 1

Statistical source data for Extended Data Fig. 1b,c.

Source Data Extended Data Fig. 2

Unmodified blots for Extended Data Fig. 2c.

Source Data Extended Data Fig. 2

Statistical source data for Extended Data Fig. 2d–g.

Source Data Extended Data Fig. 3

Statistical source data for Extended Data Fig. 3c,e,g,h.

Source Data Extended Data Fig. 4

Statistical source data for Extended Data Fig. 4a,d,e.

Source Data Extended Data Fig. 5

Statistical source data for Extended Data Fig. 5b,c,e–h.

Source Data Extended Data Fig. 6

Statistical source data for Extended Data Fig. 6a,b,d.

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Wu, Z., Chen, L., Guo, W. et al. Oral mitochondrial transplantation using nanomotors to treat ischaemic heart disease. Nat. Nanotechnol. 19, 1375–1385 (2024). https://doi.org/10.1038/s41565-024-01681-7

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