ROS-initiated chemiluminescence-driven payload release from macrocycle-based Azo-containing polymer nanocapsules

Reactive oxygen species (ROS) overproduction is involved in many pathological processes, particularly in inflammatory diseases. Therefore, ROS-responsive nanocarriers for specific drug release have been highly sought after. Herein we developed a ROS-responsive drug delivery system based on covalently self-assembled polymer nanocapsules (Azo-NCs) formed via crosslinking macrocyclic cucurbit[6]urils by a photo-sensitive azobenzene derivative (Azo). Luminol, a chemiluminescent molecule activatable by ROS, was co-loaded into Azo-NCs together with a therapeutic payload. When exposed to high ROS concentration that is typically encountered in inflammatory cells or tissues, the ROS-initiated blue chemiluminescence of luminol drives photoisomerization of the Azo groups within Azo-NCs, leading to Azo-NCs' surface transformation and distortion of the nanostructure, and subsequent payload release. As a proof-of-concept, ROS-responsive payload release from luminol-loaded Azo-NCs in inflammatory cells and zebrafish was demonstrated, showing promising anti-inflammatory effects in vitro and in vivo.