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Conventional photoacoustic (PA) contrast agents have been used to improve detection sensitivity relative to endogenous absorbers, but their fixed optical properties limit adaptation to heterogeneous or evolving disease microenvironments. Activatable PAI contrast agents overcome this drawback by switching their absorbance spectra in real time in response to exogenous triggers (near\u2010infrared light, heat, ultrasound, and electromagnetic fields) or endogenous microenvironmental cues (hypoxia, pH, reactive oxygen species, glutathione, and disease\u2010related enzymes). These dynamic features extend PAI beyond static signal enhancement, enabling user\u2010controlled activation, suppression of background interference, and access to functional or molecular biomarkers that conventional agents cannot provide. This review surveys recent advances in the molecular design, activation chemistry, and biomedical applications of these \u201cactivatable\u201d probes, highlighting strategies for noninvasive diagnosis, multimodal imaging, remote actuation, and synergistic theranostics. Looking ahead, the next frontier lies in pathology\u2010tailored probes that can noninvasively reveal biomarkers inaccessible to current methods, as illustrated by early successes in atherosclerosis imaging. Achieving this translation will require optimizing probe safety and clearance, standardizing characterization protocols, and integrating hybrid imaging platforms with quantitative PA tomography to generate reliable diagnostic metrics.<\/jats:p>","DOI":"10.1002\/smo2.70024","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T12:56:01Z","timestamp":1761828961000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Activatable smart contrast agents for photoacoustic imaging"],"prefix":"10.1002","volume":"4","author":[{"given":"Donghyeon","family":"Oh","sequence":"first","affiliation":[{"name":"Departments of Electrical Engineering Convergence IT Engineering, Mechanical Engineering, Medical Science and Engineering Pohang University of Science and Technology (POSTECH)  Pohang Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihye","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemistry POSTECH  Pohang Republic of Korea"},{"name":"POSTECH\u2010CATHOLIC Biomedical Engineering Institute  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suyoung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Nanoscience Ewha Womans University  Seoul Republic of Korea"},{"name":"Graduate Program in Innovative Biomaterials Convergence Ewha Womans University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1728-3970","authenticated-orcid":false,"given":"Juyoung","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Nanoscience Ewha Womans University  Seoul Republic of Korea"},{"name":"Graduate Program in Innovative Biomaterials Convergence Ewha Womans University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won Jong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemistry POSTECH  Pohang Republic of Korea"},{"name":"POSTECH\u2010CATHOLIC Biomedical Engineering Institute  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chulhong","family":"Kim","sequence":"additional","affiliation":[{"name":"Departments of Electrical Engineering Convergence IT Engineering, Mechanical Engineering, Medical Science and Engineering Pohang University of Science and Technology (POSTECH)  Pohang Republic of Korea"},{"name":"POSTECH\u2010CATHOLIC Biomedical Engineering Institute  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"e_1_2_7_2_1","volume-title":"Biomedical Optics: Principles and Imaging","author":"Wang L. 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