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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月8日

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  • Jingjie Liu,
  • Jiaqi Qin,
  • Wenxia Zheng,
  • Xiaojuan Wang,
  • Zhaohan Wei,
  • Zixiang Xie,
  • Tingwei Yan,
  • Xin Li,
  • Ziqiao Ding,
  • Haojie Liu,
  • Zhiheng Cai,
  • Shanmiao Gou,
  • Xiangliang Yang,
  • Tuying Yong,
  • Lu Gan

摘要

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.