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However, its redox\u2010based mechanism remains underexplored. Here, it is revealed that DOX specifically binds to the heme center of cytochrome P450 (CYP450) enzymes via its quinone moiety, enabling electron transfer that catalyzes molecular oxygen into superoxide anions (O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2022\u2212<\/jats:sup>\n                    ). To enhance this process, mesoporous polydopamine (mPDA) is introduced as an electron\u2010rich scaffold, amplifying electron flow to DOX. Furthermore, L\u2010arginine (L\u2010Arg) is co\u2010delivered to supply nitric oxide (NO), which reacts with O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2022\u2212<\/jats:sup>\n                    to generate peroxynitrite (ONOO\n                    <jats:sup>\u2212<\/jats:sup>\n                    ), a stable, highly cytotoxic ROS. ONOO\n                    <jats:sup>\u2212<\/jats:sup>\n                    further activates matrix metalloproteinase (MMP), promoting extracellular matrix degradation and facilitating drug\/oxygen penetration. Moreover, the system enables multimodal tumor therapy by integrating DOX\u2010based chemotherapy, nitric oxide (NO) gas therapy, and mPDA\u2010mediated photothermal therapy. This work unveils a novel DOX\u2010CYP450 electron transfer mechanism and establishes a synergistic therapeutic paradigm to overcome tumor microenvironmental barriers and enhance treatment efficacy.\n                  <\/jats:p>","DOI":"10.1002\/smtd.202501358","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T07:26:36Z","timestamp":1763018796000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Unveiling a Doxorubicin\u2010Cytochrome P450 Electron Transfer Pathway for Synergistic Multimodal Tumor Therapy"],"prefix":"10.1002","volume":"9","author":[{"given":"Wenbo","family":"Yin","sequence":"first","affiliation":[{"name":"State Key Lab of Electroanalytical Chemistry Changchun Institute of Applied Chemistry Chinese Academy of Sciences  Changchun Jilin 130022 China"},{"name":"School of Applied Chemistry and Engineering University of Science and Technology of China  Hefei Anhui 230026 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zonghang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Science and Engineering Shenzhen Key Laboratory of Functional Aggregate Materials The Chinese University of Hong Kong  Shenzhen Guangdong 518172 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangjie","family":"An","sequence":"additional","affiliation":[{"name":"State Key Lab of Electroanalytical Chemistry Changchun Institute of Applied Chemistry Chinese Academy of Sciences  Changchun Jilin 130022 China"},{"name":"School of Applied Chemistry and Engineering University of Science and Technology of China  Hefei Anhui 230026 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Song","sequence":"additional","affiliation":[{"name":"State Key Lab of Electroanalytical Chemistry Changchun Institute of Applied Chemistry Chinese Academy of Sciences  Changchun Jilin 130022 China"},{"name":"School of Applied Chemistry and Engineering University of Science and Technology of China  Hefei Anhui 230026 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2803-488X","authenticated-orcid":false,"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Molecular Recognition and Biosensing Frontiers Science Center for New Organic Matter College of Chemistry Nankai University  Tianjin 300071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiue","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Lab of Electroanalytical Chemistry Changchun Institute of Applied Chemistry Chinese Academy of Sciences  Changchun Jilin 130022 China"},{"name":"School of Applied Chemistry and Engineering University of Science and Technology of China  Hefei Anhui 230026 China"},{"name":"Tianjin Key Laboratory of Molecular Recognition and Biosensing Frontiers Science Center for New Organic Matter College of Chemistry Nankai University  Tianjin 300071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2919"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.6093249"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2021.03.018"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5NR00290G"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpclett.2c02272"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111708"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.201701070"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtbio.2022.100364"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.201802070"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202418928"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201708007"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.5b00407"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cej.2019.123632"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsami.4c08491"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nantod.2024.102151"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsabm.4c01165"},{"key":"e_1_2_8_17_1","volume":"15","author":"Opoku\u2010Damoah Y.","year":"2023","journal-title":"ACS Appl. 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