Pyroptosis activation by photodynamic-boosted nanocatalytic medicine favors malignancy recession

Abstract

Although pyroptosis as a newly-emerging but burgeoning programmed cell death fashion has been extensively accepted to outperform apoptosis in inducing rapid and complete cell deaths, potentiating immunity and mitigating resistance, its contribution is low. Therefore, the demand to elevate pyroptosis level is highly desirable and highlighted. Herein, a RGD-modified and pyroptosis-engineered theranostic agent (PETA) consisting of Fe3O4-embedded magnetic mesoporous silica nanoparticles (MMSN) vehicles and chlorin e6 (Ce6) photosensitizers (i.e., MMSN-cRGD@Ce6) is established to heighten ROS level for inducing pyroptosis by Ce6-mediated photodynamic process. Inspiringly, Fe3O4-mediated nanocatalytic medicine contributes to O2 release and hypoxia mitigation, which liberates hypoxia-induced resistances to ROS production and further favors ROS production. Consequently, ROS-activated pyroptosis is accessible to circumvent the hypoxia-induced resistance to ROS-activated apoptosis especially when uniting with cRGD-enhanced active targeting, which significantly represses malignant breast cancer in vitro and in vivo. The design principles of targeted PETAs can serve as a general method to develop new pyroptosis-highlighted theranostic agents, and coincidently indicate that pyroptosis contribution should be surveyed to veritably and comprehensively reflect death pathway when investigating ROS-based anti-tumor pathways.