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In recent decades, many photosensitizers have been developed and applied in PDT. However, PDT is still limited by light penetration depth, although many near-infrared photosensitizers have emerged. The chemiluminescence-mediated PDT (CL-PDT) system has recently received attention because it does not require an external light source to achieve targeted PDT. This review focuses on the rational design of organic CL-PDT systems. Specifically, PDT types, light wavelength, the chemiluminescence concept and principle, and the design of CL-PDT systems are introduced. Furthermore, chemiluminescent fraction examples, strategies for combining chemiluminescence with PDT, and current cellular and animal applications are highlighted. Finally, the current challenges and possible solutions to CL-PDT systems are discussed.<\/jats:p>","DOI":"10.3390\/ijms232012556","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T20:32:23Z","timestamp":1666211543000},"page":"12556","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Chemiluminescence in Combination with Organic Photosensitizers: Beyond the Light Penetration Depth Limit of Photodynamic Therapy"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6143-6284","authenticated-orcid":false,"given":"Jie","family":"Gao","sequence":"first","affiliation":[{"name":"Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi 563000, China"},{"name":"Key Laboratory of Biocatalysis & 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