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Development of an Intracellular Nitric Oxide-Donating Cell-Penetrating Polypeptide as an Immunogenic Cell Death

Naeun Kim1, Susam Lee1, Heewon Park1

  • 1Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.

ACS Applied Bio Materials
|October 11, 2024
PubMed

Insights

This study introduces poly(l-guanidine) (PLG), a novel polypeptide that generates nitric oxide (NO) within tumor cells. This NO then effectively triggers immunogenic cell death (ICD) via endoplasmic reticulum stress and mitochondrial pathways.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Nitric oxide (NO) induces tumor cell immunogenic cell death (ICD) via endoplasmic reticulum (ER) stress and mitochondrial outer membrane permeabilization (MOMP).
  • The instability of NO poses challenges for direct therapeutic delivery.
  • Developing effective NO delivery systems is crucial for cancer immunotherapy.

Purpose of the Study:

  • To develop a novel, cell-penetrating polypeptide-based nitric oxide (NO) donor for inducing immunogenic cell death (ICD) in tumor cells.
  • To investigate the mechanisms by which the NO donor generates NO intracellularly and triggers ICD.

Main Methods:

  • Synthesis of a cell-penetrating polypeptide, poly(l-guanidine) (PLG).
  • Investigation of PLG's ability to penetrate cells and generate reactive oxygen species (ROS).
  • Analysis of NO production via guanidine oxidation catalyzed by intracellular ROS.
  • Assessment of ICD induction through ER stress and MOMP markers.

Main Results:

  • Helical PLG demonstrated spontaneous cell penetration and intracellular ROS generation.
  • PLG effectively produced NO through self-inducible guanidine oxidation within cells.
  • The generated NO induced ICD by activating ER stress and MOMP-dependent pathways.

Conclusions:

  • Poly(l-guanidine) (PLG) serves as an effective intracellular nitric oxide (NO) donor.
  • PLG-mediated NO generation successfully induces tumor cell immunogenic cell death (ICD).
  • The findings highlight PLG as a promising platform for cancer therapy leveraging NO-induced ICD.
Keywords:
ER stressICDMOMPcell-penetrating polypeptideguanidine oxidationnitric oxide

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