Activatable Self-Amplifying ROS Nanoplatform for Augmented Cerenkov-induced Photodynamic Therapy

Abstract

Cerenkov radiation induced photodynamic therapy (CR-PDT) offers a promising approach to overcome the dependency on external light sources and associated tissue penetration limitations. However, the therapeutic efficacy of CR-PDT is constrained by tumor hypoxia and the intrinsically short half-life and limited diffusion distance of reactive oxygen species (ROS). Herein, we propose a tumor acidity-triggered, mitochondria-targeted CR-PDT strategy to amplify the ROS generation for enhanced therapeutic efficacy. The mitochondria-targeted photosensitizers (TTCPP) are encapsulated within amphiphilic polymers, functionalized with acidity-responsive moiety and 131I labeling group, forming 131I-TTCPP nanoparticles (131I-TTCPP NPs). Under physiological conditions, 131I-TTCPP NPs exhibit minimal phototoxicity due to aggregation-caused quenching (ACQ). Upon encountering the acidic tumor microenvironment, 131I-TTCPP NPs disintegrate, restoring the photodynamic activity of TTCPP. Compared to non-targeted photosensitizers TCPP, the released mitochondria-targeted TTCPP effectively localizes to mitochondria and undergoes self-activation by 131I, generating significantly higher levels of ROS, which results in more severe mitochondrial dysfunction and enhanced apoptosis. Our findings demonstrate that coupling mitochondria targeting with self-activated CR-PDT provides a more effective and safer option for cancer treatment.