Targeted intervention in nerve–cancer crosstalk enhances pancreatic cancer chemotherapy

IF 38.1 1区 材料科学 Q1 MATERIALS SCIENCE, MULTIDISCIPLINARY Nature nanotechnology Pub Date : 2024-11-04 DOI:10.1038/s41565-024-01803-1
Jiaqi Qin, Jingjie Liu, Zhaohan Wei, Xin Li, Zhaoxia Chen, Jianye Li, Wenxia Zheng, Haojie Liu, Shiyi Xu, Tuying Yong, Ben Zhao, Shanmiao Gou, Shenghong Ju, Gao-Jun Teng, Xiangliang Yang, Lu Gan
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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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靶向干预神经-癌症串扰可增强胰腺癌化疗效果
神经-癌症串扰因其对肿瘤生长、转移和耐药性的影响而备受关注。在错综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然是胰腺癌的一大挑战。在这里,我们开发了大肠杆菌 Nissle 1917 衍生的外膜囊泡,这些囊泡与神经结合肽 NP41 连接,并装载了肌球蛋白受体激酶(Trk)抑制剂 larotrectinib(Lar@NP-OMVs),用于靶向肿瘤相关神经。Lar@NP-OMVs 通过破坏神经营养素/Trk 信号通路,实现了有效的神经干预,减少了神经元的生长。此外,OMV 介导的 M2 型肿瘤相关巨噬细胞重新极化为 M1 型表型会导致神经损伤,从而进一步加强 Lar@NP-OMV 诱导的神经干预,抑制神经触发的胰腺癌细胞增殖和迁移以及血管生成。利用这一策略,Lar@NP-OMVs 能显著减少吉西他滨在肿瘤微环境中促进的神经浸润和神经元生长,从而提高胰腺癌的化疗疗效。这项研究揭示了神经靶向治疗干预增强胰腺癌治疗的潜在途径。
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来源期刊
Nature nanotechnology
Nature nanotechnology 工程技术-材料科学:综合
CiteScore
59.70
自引率
0.80%
发文量
196
审稿时长
4-8 weeks
期刊介绍: Nature Nanotechnology is a prestigious journal that publishes high-quality papers in various areas of nanoscience and nanotechnology. The journal focuses on the design, characterization, and production of structures, devices, and systems that manipulate and control materials at atomic, molecular, and macromolecular scales. It encompasses both bottom-up and top-down approaches, as well as their combinations. Furthermore, Nature Nanotechnology fosters the exchange of ideas among researchers from diverse disciplines such as chemistry, physics, material science, biomedical research, engineering, and more. It promotes collaboration at the forefront of this multidisciplinary field. The journal covers a wide range of topics, from fundamental research in physics, chemistry, and biology, including computational work and simulations, to the development of innovative devices and technologies for various industrial sectors such as information technology, medicine, manufacturing, high-performance materials, energy, and environmental technologies. It includes coverage of organic, inorganic, and hybrid materials.
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