Tumor Microenvironment Activated Heptamethine Cyanine Photosensitizer for In Situ CuS Nanoparticle Generation Triggering Near Infrared Fluorescence Imaging and Synergistic Photothermal/Photodynamic Therapy

Conventional “always-on” phototherapies often suffer from insufficient tumor selectivity and suboptimal utilization of reactive oxygen species (ROS) and photothermal therapy, limiting their clinical efficacy. Herein, a novel activatable, single-component theranostic system was developed for overcoming these limitations via tumor microenvironment-triggered dual-modal phototherapy. A heptamethine cyanine-based photosensitizer, Cu-Icy-H 2 S, was rationally designed by integrating an iodo-substituted cyanine fluorophore with a Cu 2 + –cyclen complex. This molecule remains photoinactive under physiological conditions but undergoes rapid activation in the presence of elevated hydrogen sulfide (H 2 S), a tumor-associated biomarker. The H 2 S-mediated reaction triggers in situ formation of CuS nanoparticles and simultaneously liberates a photoactive cyanine derivative (Icy-H 2 S). This dual transformation enables concurrent photodynamic therapy (PDT) through ROS generation and photothermal therapy (PTT) via CuS-mediated heat production under near-infrared (NIR) irradiation. Moreover, the fluorescence of Icy-H 2 S facilitates real-time NIR imaging, allowing precise tumor localization and therapy guidance. In vivo studies in 4T1 tumor-bearing mice demonstrated significant tumor inhibition with minimal systemic toxicity, confirming the potent synergistic efficacy of the PDT-PTT combination strategy. This work introduces a reasonable design for H 2 S-responsive, single-component theranostic agents and addresses the intrinsic photothermal instability of cyanine dyes by leveraging in situ CuS nanoparticle formation for enhanced photothermal conversion.