Mitochondrial Redox Cascade-Directed Covalent NIR Fluorogenic Imaging of Therapy-Induced Senescence Integrates Tumor...

Concurrent and longitudinal imaging of therapeutic responses alongside therapy-induced damage to normal tissues during cancer treatment is of substantial clinical significance for treatment optimization and improved outcomes. However, existing approaches are largely limited to isolated imaging readouts, and, more fundamentally, there is a lack of a mechanistically shared biological denominator linking tumor response and normal tissue injury. Here, we present therapy-induced cellular senescence (TICS) as a chemically addressable, process-level surrogate and introduce a mechanistically guided covalent molecular imaging strategy for an integrated therapeutic assessment. Through systematic analysis, we reveal oxidative protein sulfenylation as a conserved biochemical feature of senescence across diverse stress models and leverage this insight to develop a dual-triggered NIR fluorogenic probe (Mito-CYD). By integrating selective covalent capture of sulfenylated proteins with MAO-A-mediated enzymatic orthogonal decaging, Mito-CYD effectively overcomes diffusion-induced signal loss inherent to conventional noncovalent probes and enables in situ visualization of senescence-associated mitochondrial dynamics with markedly enhanced signal-to-noise ratios and stable imaging over 24 h across multiple TICS models under metabolic turnover. Longitudinal tracking with Mito-CYD in tumor xenografts and cardiac injury models further demonstrates strong correlations between senescent cell burden with disease progression, therapeutic response, and treatment-related organ injury. This work establishes a mitochondrial redox-chemistry-directed covalent imaging paradigm for in vivo senescence visualization, providing a unified chemical framework for mechanistic investigation and personalized treatment of cancer and senescence-associated pathologies.