BACKGROUND: Nerves in the tumor microenvironment (TME) promote malignant phenotypes of cancer. Neuron-targeting cancer treatment strategies have garnered significant attention. However, existing pharmacological or surgical methods of denervation can lead to side effects such as pain and respiratory system issues. Targeted delivery of local anesthetics to the TME using nanotechnology to suppress nerves appears to be a promising approach. METHODS: NP-BUP, an acid-responsive nanoparticle encapsulating the local anesthetic bupivacaine, was synthetized using a nano-precipitation method. Immunofluorescence staining was employed to identify the primary types of nerves in breast tumors. In vitro, the impact of the neurotransmitter on the recruitment of macrophages by tumor supernatant is assessed using the transwell assay. ELISA assays and intracellular Ca RESULTS: The predominant type of neuron within breast tumor tissues was found to be noradrenergic neuron. Noradrenergic neuronal uptake of NP-BUP at pH 6.5 was 2.4 times higher than at pH 7.4. In vitro, NP-BUP significantly inhibited the release of norepinephrine (NE), a neurotransmitter that promotes macrophage migration, from adrenergic cells. In vivo, tumor tissues from 4T1 tumor-bearing mice treated with NP-BUP showed a significant reduction in NE content and macrophage infiltration, with tumor volume and weight decreasing by approximately 70% compared to the PBS group. CONCLUSION: Our study provides a TME pH-responsive nanoplatform for targeted suppression of neuronal control within the TME. Our results demonstrate that specifically modulating innervation within the TME can influence the growth of breast cancer.