Organelle-Targeted Photo-triggered Delivery of Acetylperoxyl Radicals for Redox Homeostasis Modulation

Abstract

Dysfunction of subcellular organelles initiates complex pathophysiological cascades and underlies numerous diseases, underscoring the need for organelle-specific therapeutic interventions. Precise spatiotemporal control of reactive oxygen species (ROS) generation within organelles offers a promising intervention approach. Herein, we report the design and synthesis of a novel series of organelle-targeted, photoactivatable acetylperoxyl radical donors (ACR575s) based on an acetyl-caged rhodamine scaffold. Blue light irradiation triggered the release of highly oxidative acetylperoxyl radicals, concomitantly generating a rhodamine dye for real-time monitoring. In vitro studies demonstrated the organelle-specific delivery of acetylperoxyl radicals, which subsequently induced concentration-dependent oxidative stress within specific subcellular compartments. Notably, this resulted in membrane damage and the modulation of macrophage polarization, providing clear evidence of the therapeutic potential of acetylperoxyl radicals in regulating redox balance and inflammatory responses. The ACR575 series provides a novel toolset for acetylperoxyl radical biology and subcellular redox regulation, enabling precise spatiotemporal control of acetylperoxyl radical-mediated oxidative stress and showing potential for applications in precise cancer therapy.