Disrupting sympathetic nerve-tumor crosstalk via biomimetic nanovesicles to augment chemotherapy efficacy under chronic stress

  • Nat Commun. 2026 May 8;17(1):6230. doi: 10.1038/s41467-026-72847-1.
Jingjie Liu  #  1  2  3  4 ,  Jiaqi Qin  #  1  5 ,  Wenxia Zheng  1 ,  Xiaojuan Wang  1 ,  Zhaohan Wei  1 ,  Zixiang Xie  1 ,  Tingwei Yan  1 ,  Xin Li  1 ,  Ziqiao Ding  1 ,  Haojie Liu  1 ,  Zhiheng Cai  1 ,  Shanmiao Gou  6 ,  Xiangliang Yang  7  8  9  10 ,  Tuying Yong  11  12  13  14 ,  Lu Gan  15  16  17  18  19
Affiliations
  • 1. Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, P. R. China.
  • 2. National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, P. R. China.
  • 3. Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, P. R. China.
  • 4. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, P. R. China.
  • 5. School of Biomedical Engineering, Anhui Medical University, Hefei, P. R. China.
  • 6. Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
  • 7. Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
  • 8. National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
  • 9. Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
  • 10. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
  • 11. Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
  • 12. National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
  • 13. Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
  • 14. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
  • 15. Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
  • 16. National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
  • 17. Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
  • 18. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
  • 19. Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
  • # Contributed equally.
PMID: 42103759 DOI: 10.1038/s41467-026-72847-1
Abstract

Chronic stress significantly impacts Cancer progression by activating the sympathetic nervous system, leading to increased tumor growth, metastasis, and resistance to chemotherapy. To address these challenges, we develop biomimetic hybrid nanovesicles (Pro@hNVs) by fusing M1 macrophage-derived vesicles with pH-sensitive liposomes (hNVs) to encapsulate the β-adrenergic receptor (ADRB) blocker propranolol (Pro). Leveraging the tumor-targeting properties of M1 macrophage-derived vesicles and their matrix metalloproteinase-mediated degradation of tumor extracellular matrix, Pro@hNVs effectively accumulate and deeply penetrate tumor tissues, followed by the release of Pro in response to the acidic tumor microenvironment. Pro subsequently inhibits the sympathetic nerve-cancer cell crosstalk by blocking ADRB2 signaling. Meanwhile, Pro@hNVs effectively reprogram adrenergic signal-induced M2-like tumor-associated macrophages (TAMs) into the M1 phenotype through the released Pro and hNVs, thereby amplifying TNF-mediated neurotoxicity and effectively disrupting sympathetic nerve-macrophage crosstalk. This dual-action mechanism of Pro@hNVs significantly inhibits the sympathetic nerve function promoted by gemcitabine, resulting in the improved chemotherapy efficacy and enhanced antitumor immune response under chronic stress. These findings highlight the potential of Pro@hNVs as a promising strategy to enhance chemotherapy outcomes in Cancer patients experiencing chronic stress, offering a viable therapeutic avenue for overcoming treatment resistance.

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