Qin Jiaqi, Liu Jingjie, Wei Zhaohan, Li Xin, Chen Zhaoxia, Li Jianye, Zheng Wenxia, Liu Haojie, Xu Shiyi, Yong Tuying, Zhao Ben, Gou Shanmiao, Ju Shenghong, Teng Gao-Jun, Yang Xiangliang, Gan Lu
National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Nat Nanotechnol. 2025 Feb;20(2):311-324. doi: 10.1038/s41565-024-01803-1. Epub 2024 Nov 4.
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.
神经与癌症的相互作用因其对肿瘤生长、转移和治疗耐药性的影响而受到广泛关注。在复杂的肿瘤微环境中，针对肿瘤相关神经的有效治疗策略仍是胰腺癌治疗的一大挑战。在此，我们开发了源自大肠杆菌Nissle 1917的外膜囊泡，其与神经结合肽NP41偶联，并负载原肌球蛋白受体激酶（Trk）抑制剂拉罗替尼（Lar@NP-OMVs），用于靶向肿瘤相关神经。Lar@NP-OMVs通过破坏神经营养因子/Trk信号通路实现有效的神经干预，以减少神经突生长。此外，OMV介导的M2样肿瘤相关巨噬细胞向M1样表型的重极化导致神经损伤，进一步增强了Lar@NP-OMV诱导的神经干预，从而抑制神经触发的胰腺癌细胞增殖、迁移和血管生成。利用这一策略，Lar@NP-OMVs显著减少了吉西他滨在肿瘤微环境中促进的神经浸润和神经突生长，从而提高了胰腺癌的化疗疗效。本研究为增强胰腺癌治疗的神经靶向治疗干预提供了一条潜在途径。
