Regulating Signal Pathway Triggers Circular Reactive Oxygen Species Production to Augment Oxidative Stress with Enzyme-Activated Nanoparticles

Regulating antioxidative stress pathways to augment oxidative stress and enhance antitumor therapy is highly desirable but very challenging. Herein, we initiated a multifunctional nanoparticle to regulate the Keap1-Nrf2 antioxidative stress pathway to promote cancer cell apoptosis. The OPFV-SnMP@GE11 nanoparticles were assembled by enzyme-activated OPFV-TLQ, tin mesoporphyrin (SnMP), and DSPEPEG-GE11. OPFV-SnMP@GE11 accumulated at tumor sites through specific targeting with GE11. OPFV-TLQ was specifically reduced to a photosensitizer OPFVNH2 by endocellular NAD(P)H: quinone oxidoreductase 1 (NQO1). Under irradiation, OPFV-NH2 greatly produced reactive oxygen species (ROS) through a type I mechanism, which activated the Keap1-Nrf2 signal pathway and enhanced the transcription of NQO1, resulting in a continuous and explosive generation of ROS. Additionally, SnMP inhibited the activity of heme oxygenase-1 (HO-1), further depressing anti oxidative stress. This strategy provides insight into the regulation of the signal pathway to amplify oxidative stress, paving the way to studying the molecular mechanisms of cellular activities to enhance cancer therapy.