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  3. Targeted intervention in nerve-cancer crosstalk enhances pancreatic cancer chemotherapy

Targeted intervention in nerve-cancer crosstalk enhances pancreatic cancer chemotherapy

  • Nat Nanotechnol. 2025 Feb;20(2):311-324. doi: 10.1038/s41565-024-01803-1.
Jiaqi Qin # 1,  Jingjie Liu # 1,  Zhaohan Wei 1,  Xin Li 1,  Zhaoxia Chen 1,  Jianye Li 1,  Wenxia Zheng 1,  Haojie Liu 1,  Shiyi Xu 1,  Tuying Yong 1 2 3,  Ben Zhao 4,  Shanmiao Gou 5,  Shenghong Ju 4,  Gao-Jun Teng 6,  Xiangliang Yang 7 8 9,  Lu Gan 10 11 12
Affiliations

Affiliations

  • 1 National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Cultivation and Construction Site of the State Key Laboratory of Intelligent Imaging and Interventional Medicine, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China.
  • 5 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 6 Cultivation and Construction Site of the State Key Laboratory of Intelligent Imaging and Interventional Medicine, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China. gjteng@seu.edu.cn.
  • 7 National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. yangxl@mail.hust.edu.cn.
  • 8 Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. yangxl@mail.hust.edu.cn.
  • 9 Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, China. yangxl@mail.hust.edu.cn.
  • 10 National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. lugan@mail.hust.edu.cn.
  • 11 Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. lugan@mail.hust.edu.cn.
  • 12 Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, China. lugan@mail.hust.edu.cn.
  • # Contributed equally.
PMID: 39496914 DOI: 10.1038/s41565-024-01803-1
Abstract

Nerve-cancer crosstalk has gained substantial attention owing to its impact on tumour growth, metastasis and therapy resistance. Effective therapeutic strategies targeting tumour-associated nerves within the intricate tumour microenvironment remain a major challenge in pancreatic Cancer. Here we develop Escherichia coli Nissle 1917-derived outer membrane vesicles conjugated with nerve-binding peptide NP41, loaded with the tropomyosin receptor kinase (Trk) inhibitor larotrectinib (Lar@NP-OMVs) for tumour-associated nerve targeting. Lar@NP-OMVs achieve efficient nerve intervention to diminish neurite growth by disrupting the neurotrophin/Trk signalling pathway. Moreover, OMV-mediated repolarization of M2-like tumour-associated macrophages to an M1-like phenotype results in nerve injury, further accentuating Lar@NP-OMV-induced nerve intervention to inhibit nerve-triggered proliferation and migration of pancreatic Cancer cells and angiogenesis. Leveraging this strategy, Lar@NP-OMVs significantly reduce nerve infiltration and neurite growth promoted by gemcitabine within the tumour microenvironment, leading to augmented chemotherapy efficacy in pancreatic Cancer. This study sheds light on a potential avenue for nerve-targeted therapeutic intervention for enhancing pancreatic Cancer therapy.

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