Amplifying ER Stress via Biodegradable Pseudo‐Conjugated Polymer Nanoparticles for Enhanced Sonodynamic Immunotherapy

Abstract Sonodynamic therapy (SDT), which utilizes ultrasound (US) to activate sonosensitizers for generating reactive oxygen species (ROS), demonstrates significant potential in sonodynamic immunotherapy through triggering endoplasmic reticulum (ER) stress and subsequently activating immunogenic cell death (ICD). However, its clinical translation has been constrained by the poor biodegradability of most sonosensitizers. This study reports the first biodegradable pseudo‐conjugated polymeric sonosensitizer (PSP), exhibiting exceptional biodegradability and efficient ROS production. To further boost sonodynamic immunotherapy, a protein kinase R‐like endoplasmic reticulum kinase (PERK) inhibitor GSK2606414 (PERKi) is co‐assembled with PSP to form nanoparticles (PERKi NP). In a 4T1 cancer model, PERKi NP can generate substantial ROS to induce ER stress upon US irradiation. Notably, the generated ROS trigger the release of PERKi, which inhibit PERK pathway, thereby amplifying ER stress and ultimately activating ICD‐associated immune responses. Overall, PERKi NP offer a promising strategy for sonodynamic immunotherapy by amplifying ER stress to potentiate ICD‐mediated immune activation.