Targeted intervention in nerve-cancer crosstalk enhances pancreatic cancer chemotherapy PMID: 39496914

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
7. National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. [email protected].
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. [email protected].
9. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, China. [email protected].
10. National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. [email protected].
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. [email protected].
12. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, China. [email protected].
# Contributed equally.

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.