Sympathetic nerves play a pivotal role in promoting tumor growth through crosstalk with tumor and stromal cells. Chemotherapy exacerbates the infiltration of sympathetic nerves into tumors, thereby providing a rationale for inhibiting sympathetic innervation to enhance chemotherapy. Here, we discovered that doxorubicin increases the density and activity of sympathetic nerves in breast cancer mainly by upregulating the expression of nerve growth factors (NGFs) in cancer cells. To address this, we developed a combination therapy by co-encapsulating small interfering RNA (siRNA) and doxorubicin within breast cancer-targeted poly (lactic--glycolic acid) (PLGA) nanoparticles, aiming to suppress NGF expression post-chemotherapy. Incorporating NGF blockade into the nanoplatform for chemotherapy effectively mitigated the chemotherapy-induced proliferation of sympathetic nerves. This not only bolstered the tumoricidal activity of chemotherapy, but also amplified its stimulatory impact on the antitumor immune response by increasing the infiltration of immunostimulatory cells into tumors while concurrently reducing the frequency of immunosuppressive cells. Consequently, the combined nanodrug approach, when coupled with -PD-L1 treatment, exhibited a remarkable suppression of primary and deeply metastatic tumors with minimal systematic toxicity. Importantly, the nanoplatform relieved chemotherapy-induced peripheral neuropathic pain (CIPNP) by diminishing the expression of pain mediator NGFs. In summary, this research underscores the significant potential of NGF knockdown in enhancing immunochemotherapy outcomes and presents a nanoplatform for the highly efficient and low-toxicity treatment of breast cancer.

中文翻译：

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通过纳米药物调节肿瘤神经支配可增强癌症免疫化疗并缓解化疗引起的神经性疼痛


交感神经通过与肿瘤和基质细胞的交互作用在促进肿瘤生长中发挥关键作用。化疗加剧了交感神经对肿瘤的浸润，从而为抑制交感神经支配以增强化疗提供了理论依据。在这里，我们发现阿霉素主要通过上调癌细胞中神经生长因子（NGF）的表达来增加乳腺癌交感神经的密度和活性。为了解决这个问题，我们开发了一种联合疗法，将小干扰 RNA (siRNA) 和阿霉素共同封装在乳腺癌靶向聚乳酸-乙醇酸 (PLGA) 纳米颗粒中，旨在抑制化疗后 NGF 的表达。将 NGF 阻断纳入化疗纳米平台可有效减轻化疗引起的交感神经增殖。这不仅增强了化疗的杀肿瘤活性，而且通过增加免疫刺激细胞向肿瘤的浸润，同时减少免疫抑制细胞的频率，放大了化疗对抗肿瘤免疫反应的刺激作用。因此，联合纳米药物方法与-PD-L1治疗相结合，表现出对原发性和深度转移性肿瘤的显着抑制，并且系统毒性最小。重要的是，纳米平台通过减少疼痛介质 NGF 的表达来缓解化疗引起的周围神经性疼痛 (CIPNP)。总之，这项研究强调了 NGF 敲低在增强免疫化疗效果方面的巨大潜力，并为乳腺癌的高效、低毒性治疗提供了一个纳米平台。