An energy metabolism-engaged nanomedicine maintains mitochondrial homeostasis to alleviate cellular ageing

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An energy metabolism-engaged nanomedicine maintains mitochondrial homeostasis to alleviate cellular ageing

Data availability

The authors declare that all data supporting the findings of this study are available within the article and its Supplementary Information files. Source data for Figs. 1–6 and Supplementary Figs. 1–22 are available in separate source data files. The raw transcriptome data used in this paper are deposited in the NCBI Sequence Read Archive under accession number PRJNA1270042. Source data are provided with this paper.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China 2024YFA1210400 (Y.L.), National Natural Science Foundations of China 82230030 (Y.L.), 52372174 (D.L.), Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases (C.W.), Beijing Natural Science Foundation L234017 (Y.L.), Beijing Nova Program 20240484655 (Y.L.), Key R&D Plan of Ningxia Hui Autonomous Region 2020BCG01001 (Y.L.), Peking University Medicine plus X Pilot Program-Key Technologies R&D Project 2024YXXLHGG004 (Y.L.), Peking University Clinical Medicine Plus X-Young Scholars Project PKU2024LCXQ039 (Y.L.), Innovative Research Team of High-level Local Universities in Shanghai SHSMU-ZLCX20212402 (Y.L.) and First-Class Discipline Team of Kunming Medical University 2024XKTDTS08 (Y.L.).

Author information

Authors and Affiliations

  1. Department of Orthodontics, National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, NMPA Key Laboratory for Dental Materials, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Peking University School and Hospital of Stomatology, Beijing, People’s Republic of China

    Liyuan Chen, Min Yu, He Zhang, Danqing He, Yu Wang, Chengye Ding, Xiaolan Wu, Chang Li, Shiying Zhang, Hangbo Liu, Xinmeng Shi, Ting Zhang & Yan Liu

  2. Beijing Institute of Nanoenergy and Nanosystems, Chinese Academy of Sciences, Beijing, People’s Republic of China

    Yijie Fan & Dan Luo

  3. Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, People’s Republic of China

    Nan Jiang, Min Yu & Yan Liu

  4. Biomedical Engineering Department, Peking University, Beijing, People’s Republic of China

    Xiaoshuai Huang

  5. Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, Peking University, Beijing, China

    Xiaoshuai Huang, Cunyu Wang & Yan Liu

  6. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China

    Zhengren Xu, Fanghui Zhang & Yan Liu

  7. Jonsson Comprehensive Cancer Center and Division of Oral and Systemic Health Sciences, School of Dentistry, University of California at Los Angeles, Los Angeles, CA, USA

    Cunyu Wang

Authors

  1. Liyuan Chen
  2. Yijie Fan
  3. Nan Jiang
  4. Xiaoshuai Huang
  5. Min Yu
  6. He Zhang
  7. Zhengren Xu
  8. Danqing He
  9. Yu Wang
  10. Chengye Ding
  11. Xiaolan Wu
  12. Chang Li
  13. Shiying Zhang
  14. Hangbo Liu
  15. Xinmeng Shi
  16. Fanghui Zhang
  17. Ting Zhang
  18. Dan Luo
  19. Cunyu Wang
  20. Yan Liu

Contributions

Y.L., C.W. and D.L. designed the experiments, analysed the data, and prepared and revised the paper. L.C. and Y.F. performed the experiments, analysed the data and performed the paper. M.Y. and H.Z. assisted with scaffold fabrication. N.J., X.H., Z.X., D.H., Y.W. and F.Z. assisted with cellular experiments. C.D., X.W., C.L., H.L. and T.Z. assisted with animal experiments. S.Z. and X.S. analysed the data. All authors reviewed the paper.

Corresponding authors

Correspondence to Dan Luo, Cunyu Wang or Yan Liu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Nanotechnology thanks Alessandro Prigione, Marc Wein and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 EM-eNMs regulate mitochondrial morphology and dynamics.

a, Live/dead staining of BMMSCs treated with 2 μg/mL EM-eNMs for 24 h (n = 3). b, Phalloidin staining of BMMSCs after incubating with 2 μg/mL EM-eNMs for 24 h. c, Western blotting of SOX2 and OCT4 in aged BMMSCs for 24 h. d, FT-IR spectra of EM-eNMs and EM-eNMs-FITC (The FT-IR peaks at 2940 cm−1 and 1742 cm−1 are the C-H stretching vibrational mode and C = O stretching vibrational mode in ZnDPA-FITC, respectively). e, Colocalization analysis of Mito-Tracker/EM-eNMs-FITC in Fig. 1i (n = 6). f, Mitochondrial morphology analysis (Mito-Tracker, Fig. 1k) g, Mitochondrial morphology analysis (TEM, Fig. 1k). h, Mito-tracker staining and semiquantitative analysis of mitochondrial morphology of young (P2) and old (P12) BMMSCs. i, TEM observation of the mitophagy following EM-eNMs treatment. j, Colocalization analysis of Mito-Tracker and GFP-LC3 in Fig. 1m (n = 10). k, Imaging of adenovirus-transfected GFP-LC3 (green) and Mito-Tracker (red) co-stained mitophagy, with 3MA serving as the negative control and rapamycin as the positive control. l, Semiquantitative analysis of the colocalization of Mito-Tracker and Lyso-Tracker in Fig. 1n (n = 10). m, Immunofluorescence staining of mitochondrial marker HSP60 (red) and lysosomal marker LAMP1 (green) (n = 10). n, Imaging of Mito-Tracker (red) and Lyso-Tracker (green) stained mitochondria and lysosomes, with BafA1 serving as a negative control and rapamycin as a positive control (n = 10). o, Immunofluorescence staining of the mitochondrial marker HSP60 (red) and lysosomal marker LAMP1 (green) in BMMSCs, with BafA1 serving as the negative control and rapamycin as the positive control (n = 10). p, Semiquantitative analysis of western blotting in Fig. 1p. q, Western blotting analysis of autophagy-related markers BECN1, LC3 II, and LC3 I in aged BMMSCs (P10 − 12) following EM-eNMs stimulation. r, Immunofluorescence analysis of mCherry-GFP-LC3 in EM-eNMs-treated aged BMMSCs shows increased autophagosomes (yellow) and autolysosomes (red) (n = 8). Two-sided unpaired t-tests (unless specified); one-way ANOVA (Extended Data Fig. 3e) with Tukey’s test. P values shown in figures. Biological replicates (n) are indicated.

Source data

Extended Data Fig. 2 EM-eNMs rejuvenate BMMSCs derived from elderly individuals.

a, Schematic showing the BMMSCs derived from young and elderly individuals with or without EM-eNMs treatment. b, SAβ-gal staining, immunofluorescence staining of γ-H2AX, and DCFH-DA probe analysis to observe ROS level in BMMSCs derived from young and elderly individuals with or without EM-eNMs treatment. Data are presented as mean ± s.d., n = 5 biologically independent samples, by one-way ANOVA with Tukey’s post hoc test. The P value is noted. The icon in a was created with figdraw.com.

Source data

Extended Data Fig. 3 EM-eNMs maintain BMMSC stemness and function.

a, RT-qPCR analysis of stemness-related genes SOX2 and OCT4, and osteogenesis-related genes BMP2 and RUNX2 in EM-eNMs-treated BMMSCs at P2. Data are presented as mean ± s.d., n = 3 biologically independent samples, two-sided unpaired Student’s t-test; the P value is noted. b, Immunofluorescence staining of ALP, BMP2, OCN, and VEGF of the mineralized collagen scaffolds loaded with the PBS- or EM-eNMs-treated BMMSCs in nude mice in Fig. 3p. c, Representative TEM images of barium titanium trioxide nanoparticles (BaTiO3), cadmium sulfide quantum dots (CdS), triiron tetraoxide nanoparticles (Fe3O4), gold nanoparticles (Au), carbon quantum dots (C), and silver nanoparticles (Ag). d, RT-qPCR of SOX2 and OCT4 in BMMSCs treated with different nanoparticles including BaTiO3, CdS, Fe3O4, Au, C, and Ag, and EM-eNMs-treated BMMSCs following H2O2 stimulation for 24 h. Data are presented as mean ± s.d., n = 3 biologically independent samples, by one-way ANOVA with Tukey’s post hoc test. The P value is noted.

Source data

Extended Data Fig. 4 EM-eNMs inhibit ATP levels and modulate mitophagy.

a, RT-qPCR confirming the knockdown efficiency of ATP5B siRNA. Data are presented as mean ± s.d., n = 3 biologically independent samples, by one-way ANOVA with Tukey’s post hoc test. The P value is noted. b, Western blotting of ATP5B expression in PBS- and EM-eNMs-treated BMMSCs, as well as in siNC- and siATP5B-treated BMMSCs, n = 3 biologically independent samples. c, ATP levels of aged BMMSCs treated with siNC or siATP5B. Data are presented as mean ± s.d., n = 6 biologically independent samples, two-sided unpaired Student’s t-test; the P value is noted.

Source data

Extended Data Fig. 5 EM-eNMs increase bone density in young mice.

a, Schematic illustration of animal experiment design. b, c, Representative µCT images 3D reconstructions (b) and semiquantification of trabecular bone parameters (c) in different groups. Data are presented as mean ± s.d., n = 5 biologically independent samples, two-sided unpaired Student’s t-test; the P value is noted. The icon in a was created with figdraw.com.

Source data

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Chen, L., Fan, Y., Jiang, N. et al. An energy metabolism-engaged nanomedicine maintains mitochondrial homeostasis to alleviate cellular ageing. Nat. Nanotechnol. (2025). https://doi.org/10.1038/s41565-025-01972-7

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