Nanoparticle-mediated drug delivery is especially useful for targets within endosomes because of the endosomal transport mechanisms of many nanomedicines within cells. Here, we report the design of a pH-responsive, soft polymeric nanoparticle for the targeting of acidified endosomes to precisely inhibit endosomal signalling events leading to chronic pain. In chronic pain, the substance P (SP) neurokinin 1 receptor (NK1R) redistributes from the plasma membrane to acidified endosomes, where it signals to maintain pain. Therefore, the NK1R in endosomes provides an important target for pain relief. The pH-responsive nanoparticles enter cells by clathrin- and dynamin-dependent endocytosis and accumulate in NK1R-containing endosomes. Following intrathecal injection into rodents, the nanoparticles, containing the FDA-approved NK1R antagonist aprepitant, inhibit SP-induced activation of spinal neurons and thus prevent pain transmission. Treatment with the nanoparticles leads to complete and persistent relief from nociceptive, inflammatory and neuropathic nociception and offers a much-needed non-opioid treatment option for chronic pain.

中文翻译：

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pH响应纳米颗粒靶向内体中的神经激肽1受体，以防止慢性疼痛。

由于细胞内许多纳米药物的内体转运机制，纳米粒子介导的药物递送对于内体中的靶特别有用。在这里，我们报告了针对酸化内体的pH响应，柔软的聚合物纳米颗粒的设计，以精确抑制导致慢性疼痛的内体信号传导事件。在慢性疼痛中，P（SP）神经激肽1受体（NK1R）从质膜重新分布到酸化的内体，并在其中发出信号以维持疼痛。因此，内体中的NK1R为缓解疼痛提供了重要的靶点。pH响应纳米颗粒通过网格蛋白和动力蛋白依赖性内吞作用进入细胞，并在含NK1R的内体中积累。鞘内注射到啮齿动物后，含有FDA批准的NK1R拮抗剂aprepitant的纳米颗粒，抑制SP诱导的脊神经元活化，从而防止疼痛传播。用纳米颗粒进行治疗可从伤害性，炎症性和神经性伤害感受中完全持久地缓解，并为慢性疼痛提供了急需的非阿片类药物治疗选择。