Monoamine Oxidase A-Activatable Theranostic Probe for Image-Guided Photodynamic Elimination of Senescent Tumor Cells

Cellular senescence contributes to tumor recurrence by fostering a pro-tumorigenic microenvironment after therapy. While SA-β-gal serves as a widely adopted biomarker of senescence, its inadequate specificity impedes the precision with which senolytic therapies can be directed. Here, we designed and developed a theranostic probe named DMTP-1 to target monoamine oxidase A (MAO-A), an enzyme that is upregulated in senescent tumor cells. Upon MAO-A activation, DMTP-1 is converted to a cationic product, ADMTP-1, which exhibits aggregation-induced emission (AIE) for imaging and generates reactive oxygen species (ROS) under light for photodynamic therapy (PDT). Cellular studies demonstrate that the fluorescence signal and PDT efficacy of DMTP-1 are markedly enhanced in MAO-A-overexpressing senescent tumor cells, enabling image-guided elimination of these cells. Moreover, DMTP-1 shows potent photodynamic activity in 3D multicellular tumor spheroids and enables clear visualization of senescence-associated MAO-A upregulation in a zebrafish senescence model. This MAO-A-activated probe enables specific detection and eradication of therapy-induced senescent tumor cells, offering a targeted strategy for senolytic intervention.