Aggregation-Induced Photodegradable and Hydrolyzable Photosensitizer for Cu64 Positron Emission Tomography/Photoacoustic Imaging-Guided Phototherapy Nanoplatforms with Controllable Performance

Radio imaging and optical imaging offer complementary advantages for biomedical diagnosis. However, the photosensitizers used in imaging must be degraded to reduce phototoxicity during phototherapy. Herein, we report a novel dicyanomethylene-based near-infrared photosensitizer (PS) that self-degrades via multiple pathways, including hydrolysis, aggregation-induced photodegradation, and oxidation by hypochlorous acid. To meet diverse theranostic requirements, the degradation behavior and performance of the PS were systematically regulated through co-assembly with three carriers. First, co-assembly with DSPE-PEG2000 produced a nanosystem that is stable to laser irradiation and water during multimodal diagnosis, and labeling with 64Cu enabled dual-mode photoacoustic and radio signal imaging. Second, co-assembly with PLGA-PEG5000 reduced the photodegradation rate by enabling complete degradation through hydrolysis, thereby facilitating deep-tumor phototherapy. Third, complexation with cucurbit[8]uril (CB[8]) selectively inhibited the hydrolytic properties of the photosensitizer, thereby reducing its phototoxicity through photodegradation and oxidative degradation pathways when superficial tumors are subjected to phototherapy. The phototherapeutic efficacy of the designed nanosystems was validated in a subcutaneous 4T1 tumor-bearing mouse model. The results demonstrated effective tumor inhibition with minimal phototoxicity, confirming the suitability of the developed system for safe phototherapy. Overall, this work presents a rational strategy for tuning photosensitizer degradation pathways to balance imaging performance, therapeutic efficacy, and biosafety, providing a versatile platform for multimodal theranostic applications.