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Enhanced nanoparticle delivery across vascular basement membranes of tumours using nitric oxide

Nature Biomedical Engineering volume 9, pages 1486–1501 (2025)Cite this article

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Abstract

The delivery of nanoparticles (NPs) into solid tumours is challenged by the tumour vascular basement membrane (BM), a critical barrier beneath the endothelium with robust mechanical properties resistant to conventional treatments. Here we propose an approach that uses nitric oxide (NO) to induce the opening of endothelial junctions, creating gaps between endothelial cells and enabling the navigation of NPs through these gaps. Subsequently, NO orchestrates a transient degradation of the BM encasing NP pools in a precise, localized action, allowing the enhanced passage of NPs into the tumour interstitial space through explosive eruptions. We have engineered a NO nanogenerator tailored for near-infrared laser-triggered on-demand NO release at tumour sites. Through breaching the BM barrier, this system results in an increase of clinical nanomedicines within the tumour, boosting the tumour suppression efficacy in both mouse and rabbit models. This approach delicately manages BM degradation, avoiding excessive degradation that might facilitate cancer metastasis. Our NO nanogenerator serves as a precise spatial catalytic degradation strategy for breaching the tumour vascular BM barrier, holding promise for NP delivery into non-tumour diseases.

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Fig. 1: NO induces spatial catalytic degradation of BM barriers for enhanced NP delivery into tumours.
Fig. 2: NO induces NP eruptions and facilitates NP extravasation into the tumour interstitial space.
Fig. 3: NO promotes the opening of endothelial gaps and exposes concealed BM.
Fig. 4: NO promotes NP pool formation, enabling precise spatial localization within the BM.
Fig. 5: NPs rely on activated MMPs to breach the BM barrier and induce eruption.
Fig. 6: Precise NO release from NanoNO breaches the BM barrier and induces NP eruption.
Fig. 7: NO-induced eruption improves the accumulation and therapeutic effect of NPs.

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Data availability

The main data supporting the results of this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors upon reasonable request. Source data are provided with this paper.

References

  1. Jain, R. K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 7, 653–664 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Mitchell, M. J. et al. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 20, 101–124 (2021).

    Article  CAS  PubMed  Google Scholar 

  3. Luan, N. M. N. et al. The mechanisms of nanoparticle delivery to solid tumours. Nat. Rev. Bioeng. 2, 201–213 (2024).

    Article  Google Scholar 

  4. Glassman, P. M. et al. Targeting drug delivery in the vascular system: focus on endothelium. Adv. Drug Deliv. Rev. 157, 96–117 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Wettschureck, N., Strilic, B. & Offermanns, S. Passing the vascular barrier: endothelial signaling processes controlling extravasation. Physiol. Rev. 99, 1467–1525 (2019).

    Article  CAS  PubMed  Google Scholar 

  6. Sindhwani, S. et al. The entry of nanoparticles into solid tumours. Nat. Mater. 19, 566–575 (2020).

    Article  CAS  PubMed  Google Scholar 

  7. Matsumura, Y. & Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46, 6387–6392 (1986).

    CAS  PubMed  Google Scholar 

  8. Torchilin, V. Tumor delivery of macromolecular drugs based on the EPR effect. Adv. Drug Deliv. Rev. 63, 131–135 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Wang, Q. et al. Breaking through the basement membrane barrier to improve nanotherapeutic delivery to tumours. Nat. Nanotechnol. 19, 95–105 (2024).

    Article  CAS  PubMed  Google Scholar 

  10. Rowe, R. G. & Weiss, S. J. Breaching the basement membrane: who, when and how? Trends Cell Biol. 18, 560–574 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Kelley, L. C., Lohmer, L. L., Hagedorn, E. J. & Sherwood, D. R. Traversing the basement membrane in vivo: a diversity of strategies. J. Cell Biol. 204, 291–302 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Jayadev, R. & Sherwood, D. R. Basement membranes. Curr. Biol. 27, R207–R211 (2017).

    Article  CAS  PubMed  Google Scholar 

  13. Nikolova, G., Strilic, B. & Lammert, E. The vascular niche and its basement membrane. Trends Cell Biol. 17, 19–25 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Du, B. et al. Glomerular barrier behaves as an atomically precise bandpass filter in a sub-nanometre regime. Nat. Nanotechnol. 12, 1096–1102 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Pozzi, A., Yurchenco, P. D. & Iozzo, R. V. The nature and biology of basement membranes. Matrix Biol. 57–58, 1–11 (2017).

    Article  PubMed  Google Scholar 

  16. Reuten, R. et al. Basement membrane stiffness determines metastases formation. Nat. Mater. 20, 892–903 (2021).

    Article  CAS  PubMed  Google Scholar 

  17. Chang, J. & Chaudhuri, O. Beyond proteases: basement membrane mechanics and cancer invasion. J. Cell Biol. 218, 2456–2469 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  18. Sung, Y. C. et al. Delivery of nitric oxide with a nanocarrier promotes tumour vessel normalization and potentiates anti-cancer therapies. Nat. Nanotechnol. 14, 1160–1169 (2019).

    Article  CAS  PubMed  Google Scholar 

  19. Kim, T. et al. Deep brain stimulation by blood–brain-barrier-crossing piezoelectric nanoparticles generating current and nitric oxide under focused ultrasound. Nat. Biomed. Eng. 7, 149–163 (2023).

    Article  CAS  PubMed  Google Scholar 

  20. Park, J. et al. In situ electrochemical generation of nitric oxide for neuronal modulation. Nat. Nanotechnol. 15, 690–697 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Zhu, D. et al. Nitrate-functionalized patch confers cardioprotection and improves heart repair after myocardial infarction via local nitric oxide delivery. Nat. Commun. 12, 4501 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Chen, H. et al. A nitric-oxide driven chemotactic nanomotor for enhanced immunotherapy of glioblastoma. Nat. Commun. 14, 941 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Chen, Y. et al. A tough nitric oxide-eluting hydrogel coating suppresses neointimal hyperplasia on vascular stent. Nat. Commun. 12, 7079 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Kim, J. et al. Thermosensitive hydrogel releasing nitric oxide donor and anti-CTLA-4 micelles for anti-tumor immunotherapy. Nat. Commun. 13, 1479 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Li, J. L. et al. Intravital multiphoton imaging of immune responses in the mouse ear skin. Nat. Protoc. 7, 221–234 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Jiang, W. et al. Nitric oxide induces immunogenic cell death and potentiates cancer immunotherapy. ACS Nano 16, 3881–3894 (2022).

    Article  CAS  PubMed  Google Scholar 

  27. Miller, M. A. et al. Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts. Sci. Transl. Med. 9, eaal0225 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  28. Matsumoto, Y. et al. Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery. Nat. Nanotechnol. 11, 533–538 (2016).

    Article  CAS  PubMed  Google Scholar 

  29. Otger, C., Ivar, N. & Alpha, S. Y. Adherens junctions as molecular regulators of emergent tissue mechanics. Nat. Rev. Mol. Cell Biol. 25, 252–269 (2024).

    Article  Google Scholar 

  30. Giannotta, M., Trani, M. & Dejana, E. VE-cadherin and endothelial adherens junctions: active guardians of vascular integrity. Dev. Cell 26, 441–454 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. Sidibe, A. & Imhof, B. A. VE-cadherin phosphorylation decides: vascular permeability or diapedesis. Nat. Immunol. 15, 215–217 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Orsenigo, F. et al. Phosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular permeability in vivo. Nat. Commun. 3, 1208 (2012).

    Article  PubMed  Google Scholar 

  33. Kamaly, N. et al. Development and in vivo efficacy of targeted polymeric inflammation-resolving nanoparticles. Proc. Natl Acad. Sci. USA 110, 6506–6511 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Setyawati, M. I. et al. Engineering tumoral vascular leakiness with gold nanoparticles. Nat. Commun. 14, 4269 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Quintero-Fabián, S. et al. Role of matrix metalloproteinases in angiogenesis and cancer. Front. Oncol. 9, 1370 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  36. Kessenbrock, K., Plaks, V. & Werb, Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52–67 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Vandooren, J., Geurts, N., Martens, E., Van den Steen, P. E. & Opdenakker, G. Zymography methods for visualizing hydrolytic enzymes. Nat. Methods 10, 211–220 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. Dong, X. et al. Enhanced drug delivery by nanoscale integration of a nitric oxide donor to induce tumor collagen depletion. Nano Lett. 19, 997–1008 (2019).

    Article  CAS  PubMed  Google Scholar 

  39. Ridnour, L. A. et al. Nitric oxide regulates matrix metalloproteinase-9 activity by guanylyl-cyclase-dependent and -independent pathways. Proc. Natl Acad. Sci. USA 104, 16898–16903 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Underly, R. G. et al. Pericytes as inducers of rapid, matrix metalloproteinase-9-dependent capillary damage during ischemia. J. Neurosci. 37, 129–140 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Wang, X. et al. Susceptibility of rat steatotic liver to ischemia-reperfusion is treatable with liver-selective matrix metalloproteinase inhibition. Hepatology 72, 1771–1785 (2020).

    Article  CAS  PubMed  Google Scholar 

  42. Jiang, Y. et al. Near-infrared light-triggered NO release for spinal cord injury repair. Sci. Adv. 6, eabc3513 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Malhotra, K. et al. Unlocking long-term stability of upconversion nanoparticles with biocompatible phosphonate-based polymer coatings. Nano Lett. 22, 7285–7293 (2022).

    Article  CAS  PubMed  Google Scholar 

  44. Parisi, C., Seggio, M., Fraix, A. & Sortino, S. A high-performing metal-free photoactivatable nitric oxide donor with a green fluorescent reporter. ChemPhotoChem 4, 742–748 (2020).

    Article  CAS  Google Scholar 

  45. Jiang, W. et al. Overcoming oxygen heterogeneity of tumor microenvironments to boost cancer immunotherapy by oxygen-switchable ROS/RNS nanogenerators. Nano Today 48, 101696 (2023).

    Article  CAS  Google Scholar 

  46. Shen, Z. et al. Overcoming the oxygen dilemma in photoredox catalysis: near-infrared (NIR) light-triggered peroxynitrite generation for antibacterial applications. Angew. Chem. Int. Ed. 62, e202219153 (2023).

    Article  CAS  Google Scholar 

  47. Sun, J. et al. Cascade reactions by nitric oxide and hydrogen radical for anti-hypoxia photodynamic therapy using an activatable photosensitizer. J. Am. Chem. Soc. 143, 868–878 (2021).

    Article  CAS  PubMed  Google Scholar 

  48. Kurz, A. R. M. et al. MST1-dependent vesicle trafficking regulates neutrophil transmigration through the vascular basement membrane. J. Clin. Invest. 126, 4125–4139 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  49. Liu, C. et al. mRNA-based cancer therapeutics. Nat. Rev. Cancer 23, 526–543 (2023).

    Article  PubMed  Google Scholar 

  50. Lee, Y.-R. et al. Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC–WWP1 inhibitory pathway. Science 364, eaau0159 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Lin, Y.-X. et al. Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models. Sci. Transl. Med. 13, eaba9772 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Islam, M. A. et al. Restoration of tumour-growth suppression in vivo via systemic nanoparticle-mediated delivery of PTEN mRNA. Nat. Biomed. Eng. 2, 850–864 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. He, H., Liu, L., Morin, E. E., Liu, M. & Schwendeman, A. Survey of clinical translation of cancer nanomedicines—lessons learned from successes and failures. Acc. Chem. Res. 52, 2445–2461 (2019).

    Article  CAS  PubMed  Google Scholar 

  54. Cheng, Y. H., He, C. L., Riviere, J. E., Monteiro-Riviere, N. A. & Lin, Z. M. Meta-analysis of nanoparticle delivery to tumors using a physiologically based pharmacokinetic modeling and simulation approach. ACS Nano 14, 3075–3095 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).

    Article  CAS  Google Scholar 

  56. Poon, W., Kingston, B. R., Ouyang, B., Ngo, W. & Chan, W. C. W. A framework for designing delivery systems. Nat. Nanotechnol. 15, 819–829 (2020).

    Article  CAS  PubMed  Google Scholar 

  57. Horacio, C., Junjie, L., Kanjiro, M. & Kazunori, K. Controlling the biodistribution and clearance of nanomedicines. Nat. Rev. Bioeng. 2, 214–232 (2023).

    Article  Google Scholar 

  58. Stater, E. P., Sonay, A. Y., Hart, C. & Grimm, J. The ancillary effects of nanoparticles and their implications for nanomedicine. Nat. Nanotechnol. 16, 1180–1194 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Chen, S. et al. Enhanced tumour penetration and prolonged circulation in blood of polyzwitterion–drug conjugates with cell-membrane affinity. Nat. Biomed. Eng. 5, 1019–1037 (2021).

    Article  CAS  PubMed  Google Scholar 

  60. Wang, P. G. et al. Nitric oxide donors: chemical activities and biological applications. Chem. Rev. 102, 1091–1134 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. SoRelle, R. Nobel prize awarded to scientists for nitric oxide discoveries. Circulation 98, 2365–2366 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. Hou, J. et al. Targeted delivery of nitric oxide via a ‘bump-and-hole’-based enzyme–prodrug pair. Nat. Chem. Biol. 15, 151–160 (2019).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Y.W. discloses support for the research described in this study from the National Natural Science Foundation of China (52025036 and 52495010), National Key Research and Development Program of China (2020YFA0710700 and 2022YFC2303300) and Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0490000 and XDB0940000). W.J. discloses support for the research described in this study from the National Natural Science Foundation of China (52273156 and 52473154), National Key Research and Development Program of China (2022YFC2303700 and 2024YFA1212400), Young Elite Scientists Sponsorship Program by CAST (YESS20230281), Natural Science Foundation of Anhui Province (2308085Y01), Scientific Research Project of Anhui Provincial Department of Education (2023AH030113) and Fundamental Research Funds for the Central Universities (WK9100000088). This work was partially carried out at the USTC Center for Micro- and Nanoscale Research and Fabrication and Instruments Center for Physical Science, University of Science and Technology of China.

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Author notes

  1. These authors contributed equally: Wei Jiang, Zixuan Guo, Qin Wang.

Authors and Affiliations

  1. National Key Laboratory of Immune Response and Immunotherapy, Department of Radiology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Wei Jiang, Zixuan Guo, Qin Wang, Ziqi Chen, Wang Dong, Qirui Liang, Yinghong Hao, Huimin Pan, Cici Zeng, Hang Liu & Yucai Wang

  2. Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China

    Wei Jiang, Qirui Liang & Yucai Wang

  3. Macao Institute of Materials Science and Engineering, Macau University of Science and Technology, Macau, China

    Qin Wang

  4. Anhui Province Engineering Research Center of Critical Electronic Materials, School of Chemistry and Chemical Engineering, Anhui University, Hefei, China

    Hang Liu

  5. School of Biomedical Engineering, Suzhou Institute for Advanced Research, University of Science and Technology of China, Suzhou, China

    Yucai Wang

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Contributions

W.J., Z.G. and Q.W. designed and performed the experiments and analysed the experimental data. Z.G. synthesized the mRNA. Z.C., W.D. and H.P. established the tumour models and provided transgenic reporter mice. Y.H., Q.L. and Z.C. helped with the animal experiments. W.J., Q.W. and H.L. wrote the original draft of the paper. Q.W. and Y.W. supervised the project. All authors reviewed and edited the manuscript before submission.

Corresponding authors

Correspondence to Qin Wang, Hang Liu or Yucai Wang.

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Nature Biomedical Engineering thanks Chao Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–55, Tables 1 and 2, methods and unprocessed blots and gels for Supplementary Figs. 12, 22, 35 and 37.

Reporting Summary

Supplementary Video 1

This video captures multiple eruptions at the same NP pool site in NO-treated tumours. Two consecutive on–off eruptions of varying intensity occur within 30 min, with the time indexed from the eruption’s initiation at 0 min. Imaging was performed every 0.5 min, with the normalized NP intensity shown in pseudocolour.

Supplementary Video 2

This video shows the process of NP extravasation in NO-treated 4T1 tumours. The initiation of NO injection is marked at 0 min. Imaging was performed every 0.5 min, with normalized the NP intensity shown in pseudocolour.

Supplementary Video 3

This video shows the formation process of NP pools in NO-treated 4T1 tumour vessels. This process is typically completed within 10 min. The video captures a representative field post-NO treatment, with NP pool formation defined as 0 min.

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Source Data Fig. 3

Statistical source data.

Source Data Fig. 4

Statistical source data.

Source Data Fig. 5

Statistical source data.

Source Data Fig. 6

Statistical source data.

Source Data Fig. 7

Statistical source data.

Source Data Fig. 5

Unprocessed gels.

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Jiang, W., Guo, Z., Wang, Q. et al. Enhanced nanoparticle delivery across vascular basement membranes of tumours using nitric oxide. Nat. Biomed. Eng 9, 1486–1501 (2025). https://doi.org/10.1038/s41551-025-01385-w

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