Bioorthogonally Activatable Photosensitizer for NIR Fluorescence Imaging-Guided Highly Selective Elimination of Senescent Tumor Cells and Chemotherapy Enhancement.

Chemotherapy is a primary modality in cancer treatment, but it may induce cellular senescence, which in turn triggers the release of senescence-associated secretory phenotypes (SASPs) that promote tumor growth and metastasis. To selectively identify senescent cells and mitigate their negative impact on cancer therapy, herein, we have developed a β-galactosidase (β-Gal)-activated and self-immobilizing photosensitizer CyGF-DBCO-T. This photosensitizer can be selectively activated and fluorescently label proteins in situ within senescent cells, enabling near-infrared (NIR) fluorescence imaging-guided photodynamic therapy (PDT) for the precise ablation of these cells. First, we developed an activatable NIR fluorescent probe CyGF-N₃ that can specifically in situ label senescent cells. Subsequently, DBCO-T with free radicals underwent a bioorthogonal click reaction with activated CyGF-N₃ in senescent cells to generate the photosensitizer CyO-DBCO-T. Under light irradiation, CyO-DBCO-T generated singlet oxygen (¹O₂) in situ, thereby enabling precise PDT with fluorescence guidance and photoactivation. Both CyGF-N₃ and DBCO-T were encapsulated in biotinylated liposomes (CyGF-N₃@LIP-B and DBCO-T@LIP-B), which enhanced their water solubility, tumor targeting, and in vivo circulation time. This promoted the accumulation of the probes in senescent tumor cells, thus enabling intense fluorescence imaging of tumor senescence regions in mice and enhancing the efficacy of PDT. This dual-module strategy, guided by fluorescence imaging for PDT, has achieved selective identification and precise ablation of senescent tumor cells in a chemotherapy-induced senescence model, effectively alleviating chemotherapy resistance and suppressing tumor growth.