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

ABSTRACT 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.