A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain

Nat Nanotechnol. 2019 Dec;14(12):1150-1159. doi: 10.1038/s41565-019-0568-x. Epub 2019 Nov 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aprepitant / administration & dosage*
  • Aprepitant / pharmacokinetics
  • Aprepitant / therapeutic use
  • Cell Line
  • Chronic Pain / drug therapy*
  • Chronic Pain / metabolism
  • Delayed-Action Preparations / metabolism*
  • Drug Delivery Systems
  • Endosomes / metabolism
  • HEK293 Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Male
  • Mice, Inbred C57BL
  • Nanoparticles / metabolism*
  • Neurokinin-1 Receptor Antagonists / administration & dosage*
  • Neurokinin-1 Receptor Antagonists / pharmacokinetics
  • Neurokinin-1 Receptor Antagonists / therapeutic use
  • Rats
  • Receptors, Neurokinin-1 / metabolism


  • Delayed-Action Preparations
  • Neurokinin-1 Receptor Antagonists
  • Receptors, Neurokinin-1
  • Aprepitant