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Compared to covalent coupling, physical binding utilizing noncovalent interactions provides a simple and nondestructive strategy to combine PS with enzymes. However, the mechanism of enzyme\u2013PS physical combination remains largely unknown, and physically bonded enzyme\u2013PS conjugates are rarely reported. Here, we systematically investigate the interacting behaviors of representative enzymes with one of the most popular PS of chlorin e6 (Ce6) and elucidate their binding dynamics and crucial determinants. Our results reveal that the positively charged and hydrophobic residues on the surface of enzymes are crucial determinants of Ce6 binding. In addition, we demonstrate that the positively charged surface area of enzymes can be employed as a reliable criterion for assessing and predicting the enzyme\u2013Ce6 binding affinity. Guided by this criterion, we further construct catalase\u2013Ce6 nanoconjugates (CAT\u2013Ce6 NCs) with superior stability and robust photodynamic antimicrobial capability via physical binding. In a showcase treatment of methicillin-resistant\n                    <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                    (MRSA)-infected mouse model of subcutaneous abscess, CAT\u2013Ce6 NCs enable hypoxia pathological microenvironment remodeling and bacteria elimination, realizing effective catalysis-augmented PDT. This study deciphers the physical binding mechanism of enzyme\u2013PS and establishes a theoretical framework to facilitate the design and construction of outstanding enzyme\u2013PS NCs for catalysis-augmented PDT.\n                  <\/jats:p>","DOI":"10.34133\/research.0732","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T06:33:36Z","timestamp":1747636416000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":15,"title":["Deciphering the Physical Binding Mechanism of Enzyme\u2013Photosensitizer Facilitates Catalysis-Augmented Photodynamic Therapy"],"prefix":"10.34133","volume":"8","author":[{"given":"Bingqing","family":"Jia","sequence":"first","affiliation":[{"name":"Institute of Advanced Interdisciplinary Science, School of Physics, \rShandong University, Jinan 250100, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Advanced Interdisciplinary Science, School of Physics, \rShandong University, Jinan 250100, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Geng","sequence":"additional","affiliation":[{"name":"Institute of Advanced Interdisciplinary Science, School of Physics, \rShandong University, Jinan 250100, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuezheng","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Advanced Interdisciplinary Science, School of Physics, \rShandong University, Jinan 250100, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengmei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory Animal Center of Shandong University","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Qu","sequence":"additional","affiliation":[{"name":"Institute of Advanced Interdisciplinary Science, School of Physics, \rShandong University, Jinan 250100, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangdong","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Advanced Interdisciplinary Science, School of Physics, \rShandong University, Jinan 250100, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingwen","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Advanced Interdisciplinary Science, School of Physics, \rShandong University, Jinan 250100, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmei","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Centre of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, \rShandong Normal University, Jinan 250014, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weifeng","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Advanced Interdisciplinary Science, School of Physics, \rShandong University, Jinan 250100, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1551-3020","authenticated-orcid":true,"given":"Yong-Qiang","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Advanced Interdisciplinary Science, School of Physics, \rShandong University, Jinan 250100, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2025,6,3]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1039\/D0CS00173B"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","DOI":"10.1016\/j.pmatsci.2020.100685","article-title":"Recent advances in photonanomedicines for enhanced cancer photodynamic therapy","volume":"114","author":"Hu J","year":"2020","unstructured":"Hu J, Lei Q, Zhang X. Recent advances in photonanomedicines for enhanced cancer photodynamic therapy. Prog Mater Sci. 2020;114: Article 100685.","journal-title":"Prog Mater Sci"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.34133\/research.0277"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","DOI":"10.1016\/j.ccr.2022.214495","article-title":"Photodynamic-based combinatorial cancer therapy strategies: Tuning the properties of nanoplatform according to oncotherapy needs","volume":"461","author":"Chen C","year":"2022","unstructured":"Chen C, Wu C, Yu J, Zhu X, Wu Y, Liu J, Zhang Y. Photodynamic-based combinatorial cancer therapy strategies: Tuning the properties of nanoplatform according to oncotherapy needs. Coord Chem Rev. 2022;461: Article 214495.","journal-title":"Coord Chem Rev"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","DOI":"10.1016\/j.ccr.2023.215367","article-title":"Research advances in BODIPY-assembled supramolecular photosensitizers for photodynamic therapy","volume":"461","author":"Wang J","year":"2023","unstructured":"Wang J, Gong Q, Jiao L, Hao E. Research advances in BODIPY-assembled supramolecular photosensitizers for photodynamic therapy. Coord Chem Rev. 2023;461: Article 215367.","journal-title":"Coord Chem Rev"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1039\/C7CS00594F"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","DOI":"10.1016\/j.ccr.2022.214979","article-title":"Recent progress in the development of singlet oxygen carriers for enhanced photodynamic therapy","volume":"478","author":"Li G","year":"2023","unstructured":"Li G, Wu M, Xu Y, Wang Q, Liu J, Zhou X, Ji H, Tang Q, Gu X, Liu S, et al. 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