Development of an\nIntracellular Nitric Oxide-Donating\nCell-Penetrating Polypeptide as an Immunogenic Cell Death Inducer

Recently, nitric oxide (NO) has been shown to induce\nimmunogenic\ncell death (ICD) in tumor cells through endoplasmic reticulum (ER)\nstress and mitochondrial outer membrane permeabilization (MOMP). However,\nNO is unstable, making direct delivery difficult. In this study, we\ndeveloped a cell-penetrating polypeptide-based NO donor, poly(l-guanidine) (PLG). Given that the guanidine structure can be\ncatalyzed by reactive oxygen species (ROS) to produce NO, helical\nPLG plays three roles: spontaneous cell penetration, intracellular\nROS generation to produce NO, and induction of ICD. The results revealed\nthat helical PLG generates NO inside the cell by self-inducible guanidine\noxidation and that NO effectively elicits ICD by ER stress- and MOMP-dependent\nintertwined mechanisms.