In Situ Synthesis of a Tumor Microenvironment-Activated Radiosensitizing Cu2-xS/LDH Probe for Photoacoustic Imaging-Guided Radiotherapy.

The efficient delivery of theranostic nanoprobes to tumor sites remains a major challenge, often hindering precise tumor imaging and effective treatment. In this study, we present a novel strategy for the in situ generation of imaging and radiosensitizing nanoprobes inside tumors, enabling responsive photoacoustic imaging and targeted radiotherapy. The designed organic-inorganic hybrid nanoprobe is composed of a copper-based layered double hydroxide (Cu-LDH) intercalated with the near-infrared organic dye IR-806, serving as a photoacoustic imaging agent (designated as CAL-IR). Upon exposure to hydrogen sulfide (H2S) in colorectal tumor microenvironments, the nanoprobe undergoes activation and transforms in situ into copper sulfide (Cu2 - xS) nanoparticles. The newly formed Cu2 - xS/LDH heterojunction nanostructure exhibits significantly enhanced near-infrared absorption, while concurrently promoting radiotherapy efficacy through multiple mechanisms: consumption of endogenous H2S, reduction of X-ray attenuation, and intrinsic radiosensitization. This unique system allows high-contrast photoacoustic imaging and, consequently, achieves improved radiotherapy outcomes in mouse models of colorectal cancer, with minimal off-target effects. These results underscore the promising clinical potential of CAL-IR for precision tumor imaging and enhanced radiotherapy.