An activatable self-amplifying ROS nanoplatform for augmented Cerenkov radiation-induced photodynamic therapy

Cerenkov radiation-induced photodynamic therapy (CR-PDT) offers a promising approach for overcoming 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 ROS generation for enhanced therapeutic efficacy. The mitochondria-targeted photosensitizer (TTCPP) is encapsulated within amphiphilic polymers functionalized with an acidity-responsive moiety and a 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 the non-targeted photosensitizer 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 mitochondrion targeting with self-activated CR-PDT provides a more effective and safer option for cancer treatment.