Beyond Tumor Accumulation: Molecularly Targeted and Activatable Photoacoustic Contrast Agents

Abstract Photoacoustic imaging (PAI) combines optical absorption with ultrasonic detection and has emerged as a powerful platform for noninvasive molecular imaging. The clinical value of a photoacoustic contrast agent (PACA) is not only determined by tumoral accumulation, but also by whether it can generate sufficient target-to-background contrast. In practice, PACAs can be designed to detect tumor-associated biomarkers in two complementary strategies. Molecularly targeted PACAs rely on specific biological recognition to enhance probe localization or retention, whereas an activatable probe generates photoacoustic signals only in response to a disease-related biochemical trigger. Recent studies further show that molecular targeting and activatable sensing can be integrated within a single probe, for example, by combining receptor recognition with activatable, ratiometric, or photo switchable signal generation. We argue that next-generation PACAs should move beyond maximizing tumor uptake toward maximizing biologically informative target-to-background contrast under clinically realistic imaging conditions.