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Targeted intervention in nerve–cancer crosstalk enhances pancreatic cancer chemotherapy

Nature Nanotechnology volume 20, pages 311–324 (2025)Cite this article

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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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Fig. 1: Tumour innervation in a pancreatic tumour.
Fig. 2: Efficient inhibition of nerve function by Lar@NP-OMVs in vitro.
Fig. 3: Efficient inhibition of cancer cell growth and migration as well as angiogenesis by Lar@NP-OMV-treated nerves.
Fig. 4: Efficient inhibition of nerve function by Lar@NP-OMV-repolarized M2-like macrophages.
Fig. 5: Efficient anticancer activity and improved tumour microenvironment by Lar@NP-OMVs in orthotopic Panc02 tumour-bearing mice.
Fig. 6: Potent anticancer activity and improved tumour microenvironment by combination of GEM and Lar@NP-OMVs in orthotopic Panc02 tumour-bearing mice.

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Data availability

All data supporting the findings in this study are available within this article and its Supplementary Information. The raw transcriptome data used in this paper were deposited in the NCBI Sequence Read Archive under accession number PRJNA1082402. Due to the very large file size and volume of data, the remaining raw data supporting the findings of this study are available from the corresponding authors upon reasonable request. Source data are provided with this paper.

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Acknowledgements

This work was supported by National Key R&D Program of China (2022YFA1206000 to T.Y., 2020YFA0710700 to L.G., 2021YFA1201200 to T.Y. and 2022YFA1206100 to X.Y.), National Natural Science Foundation of China (82272844 to L.G., 82073796 and 81627901 to X.Y., 82330060 and 92359304 to S.J.) and Program for HUST Academic Frontier Youth Team (2018QYTD01 to L.G.). We thank J. Zhao (Huazhong University of Science and Technology, Wuhan, China) for providing the KPC cells. We thank the Research Core Facilities for Life Science (HUST), Optical Bioimaging Core Facility of WNLO-HUST and the Analytical and Testing Center of Huazhong University of Science and Technology for related analysis.

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Author notes

  1. These authors contributed equally: Jiaqi Qin, Jingjie Liu.

Authors and Affiliations

  1. National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China

    Jiaqi Qin, Jingjie Liu, Zhaohan Wei, Xin Li, Zhaoxia Chen, Jianye Li, Wenxia Zheng, Haojie Liu, Shiyi Xu, Tuying Yong, Xiangliang Yang & Lu Gan

  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

    Tuying Yong, Xiangliang Yang & Lu Gan

  3. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, China

    Tuying Yong, Xiangliang Yang & Lu Gan

  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

    Ben Zhao, Shenghong Ju & Gao-Jun Teng

  5. Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Shanmiao Gou

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Contributions

L.G., X.Y. and J.Q. designed the project. J.Q., J. Liu, Z.W., X.L., Z.C., J. Li, W.Z., H.L., S.X., T.Y. and B.Z performed the experiments. J.Q., J. Liu, S.G., S.J., G.-J.T., X.Y. and L.G. analysed and interpreted the data. J.Q. and L.G. wrote the paper.

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Correspondence to Gao-Jun Teng, Xiangliang Yang or Lu Gan.

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Extended data

Extended Data Fig. 1 Characterization of Lar@NP-OMVs.

a Morphology of OMVs, NP-OMVs, Lar@OMVs and Lar@NP-OMVs by TEM. Scale bar, 100 nm. Images are representative of three independent samples. b,c Size distribution (b) and zeta potential (c) of OMVs, NP-OMVs, Lar@OMVs and Lar@NP-OMVs by NTA and DLS analysis, respectively. Data are presented as means ± s.d. (n = 3 independent samples). d In vitro Lar release of Lar@OMVs and Lar@NP-OMVs in PBS at different pH values. Data are presented as means ± s.d. (n = 3 independent samples). e,f Hydrodynamic diameter (e) and zeta potential (f) of OMVs, NP-OMVs, Lar@OMVs and Lar@NP-OMVs in PBS with 10% mouse serum for different time intervals by DLS analysis. Data are presented as means ± s.d. (n = 3 independent samples).

Source data

Extended Data Fig. 2 Nerve targeting capability of Lar@MP-OMVs.

a DiD mean fluorescence intensity (MFI) in PC12 cells, DRG neural cells, Panc02 cells and HUVECs after treatment with DiD-labeled OMVs or NP-OMVs for 6 h. Data are presented as means ± s.d. (n = 4 biologically independent samples). b Relative Lar content in PC12 cells, DRG neural cells, Panc02 cells and HUVECs after treatment with free Lar, Lar@OMVs or Lar@NP-OMVs for 6 h by HPLC. Data are presented as means ± s.d. (n = 3 biologically independent samples). c,d In vivo representative IR780 imaging (c) and fluorescence intensity (d) of tumours in orthotopic Panc02 tumour-bearing mice at different time intervals after intravenous injection of IR780-labeled OMVs or NP-OMVs. Data are presented as means ± s.d. for d (n = 3 mice per group). e,f Ex vivo IR780 imaging (e) and fluorescence intensity (f) of the major organs and tumours of orthotopic Panc02 tumour-bearing mice at 72 h after treatment indicated in c. Data are presented as means ± s.d. for f (n = 3 mice per group). g,h Representative images (g) and quantification (h) of the co-localization of IR780-labeled OMVs or NP-OMVs with β3-tubulin-labeled nerves in tumour tissues of orthotopic Panc02 tumour-bearing mice at 72 h after treatment indicated in c. Images are representative of three independent samples. Scale bars, 50 µm for g. Data are presented as means ± s.d. for h (n = 12 fields in total from 3 mice). The P values in a, b, d and f were determined using two-way ANOVA followed by Tukey’s multiple comparisons test. The P value in h was determined using unpaired two-tailed Student's t-test.

Source data

Extended Data Fig. 3 Efficient inhibition of tumour cell proliferation and improved tumour microenvironment by combination of GEM and Lar@NP-OMVs in fresh tumour slices from pancreatic cancer patient.

a,c Representative immunofluorescence images of GAP43 (a) and β3-tubulin (c) in slices from pancreatic cancer patient-derived tumour after treatment with PBS, GEM, Lar@NP-OMVs or combination of GEM and Lar@NP-OMVs for 4 days. The cell nuclei were stained with DAPI (blue). Scale bars, 50 µm. b,d Quantification of GAP43+ (b) and β3-tubulin+ (d) areas in tumour slices from pancreatic cancer patient after treatment indicated in a. Data are presented as means ± s.d. (n = 10 fields in total from 3 biologically independent samples). e-g Percentages of M1-like TAMs (e), M2-like TAMs (f) and proliferating tumour cells (g) in tumour slices from pancreatic cancer patient after treatment indicated in a by flow cytometry. Data are presented as means ± s. d. (n = 3 biologically independent samples). h,i Representative immunofluorescence images (h) and numbers (i) of MUC1+Ki67+ cells in tumour slices from pancreatic cancer patient after treatment indicated in a. The tumour slices were stained with anti-MUC1 antibody (green) and anti-Ki67 antibody (red). The cell nuclei were stained with DAPI (blue). Scale bars, 50 µm for h. Data are presented as means ± s.d. for i (n = 6 fields in total from 3 biologically independent samples). Images in a, c and h are representative of three independent experiments. The P values in b, d-g and i were determined using one-way ANOVA followed by Tukey’s multiple comparisons test.

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Qin, J., Liu, J., Wei, Z. et al. Targeted intervention in nerve–cancer crosstalk enhances pancreatic cancer chemotherapy. Nat. Nanotechnol. 20, 311–324 (2025). https://doi.org/10.1038/s41565-024-01803-1

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