A Real-Time Cell Death Self-Reporting Theranostic Agent for Dynamic Optimization of Photodynamic Therapy

The therapeutic efficiency of photodynamic therapy (PDT) hinges on the drug-light interval (DLI), yet conventional approaches relying on photosensitizer accumulation often lead to suboptimal irradiation and adverse side effects. Here, a real-time cell death self-reporting photodynamic theranostic nanoagent (CDPN) is presented that dynamically monitors extracellular potassium ion ([K⁺] ex ) fluctuations as direct indicators of tumor cell death. By exploiting [K⁺] ex dyshomeostasis associated with apoptosis and necrosis, CDPN combines a photosensitizer and a potassium-sensitive fluorophore within mesoporous silica nanoparticles, encapsulated by a K⁺-selective membrane for enhanced specificity. In vitro and in vivo studies validate that [K⁺] ex dynamics closely correlate with cell death, enabling precise evaluation of PDT efficacy and data-driven optimization of the DLI. Using a breast cancer model, CDPN-guided adjustments identify optimized DLI conditions, achieving significantly improved therapeutic outcomes. This study introduces a new paradigm for PDT, establishing a real-time, adaptable strategy for guiding treatment parameters and advancing precision oncology.