{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T10:54:19Z","timestamp":1791111259056,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Cancer remains a major global health threat. Targeted protein degradation (TPD) has revolutionized the modulation of protein function in therapeutic development. Nevertheless, the design of current TPD agents continues to face challenges, including hook effects and, more critically, the frequent lack of spatial and temporal precision required for in vivo applications. Herein, we report a photoactivatable targeted degradation (PATD) strategy and describe the iterative optimization of compound\n                    <jats:bold>9<\/jats:bold>\n                    , the first two\u2010photon\u2010excited BRD4 photodegrader, achieved through molecular engineering of the photosensitizer core, auxiliary ligands, and linkers. Notably, BRD4 degradation downregulates GPX4 transcription, promoting lipid peroxidation and thereby inducing ferro\u2010aging, while simultaneously triggering chemo\u2010aging via histone H3 cleavage, which leads to DNA damage and cell cycle arrest. This dual\u2010aging mechanism accelerates tumor cell senescence, enabling synergistic seno\u2010immunotherapy. Beyond conventional photosensitizers that primarily elicit immunogenic cell death (ICD) alone, complex\n                    <jats:bold>9<\/jats:bold>\n                    integrates senescence\u2010driven immunity with ICD\u2010mediated antitumor immunity. This combined immunostimulatory strategy elicits robust systemic antitumor responses and achieves amplified therapeutic efficacy in patient\u2010derived organoids (PDOs), presenting a new paradigm for precision targeted protein degradation in therapy\u2010resistant tumors.\n                  <\/jats:p>","DOI":"10.1002\/anie.2645239","type":"journal-article","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T10:25:35Z","timestamp":1791109535000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Iterative Optimization of Photoactivatable BRD4 Degraders for Aging\u2010Amplified Immunotherapy in Patient\u2010Derived Lung Cancer Organoids"],"prefix":"10.1002","author":[{"given":"Jinrong","family":"Yang","sequence":"first","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry Sun Yat\u2010Sen University  Guangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fa","family":"Wang","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry Sun Yat\u2010Sen University  Guangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shufei","family":"Li","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Applied Surface and Colloid Chemistry of Ministry of Education, School of Chemistry and Chemical Engineering Shaanxi Normal University  Xi'an P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Xiong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Clean Chemistry Technology of Guangdong Regular Higher Education Institutions, School of Chemical Engineering and Light Industry Guangdong University of Technology  Guangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9600-1045","authenticated-orcid":false,"given":"Taihong","family":"Liu","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Applied Surface and Colloid Chemistry of Ministry of Education, School of Chemistry and Chemical Engineering Shaanxi Normal University  Xi'an P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5219-9195","authenticated-orcid":false,"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry Sun Yat\u2010Sen University  Guangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4153-5303","authenticated-orcid":false,"given":"Hui","family":"Chao","sequence":"additional","affiliation":[{"name":"College of Chemistry and Materials Science, State Key Laboratory of Bioactive Molecules and Druggability Assessment Jinan University  Guangzhou P. R. China"},{"name":"MOE Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, School of Chemistry and Chemical Engineering Hunan University of Science and Technology  Xiangtan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41568-025-00817-8","article-title":"Targeted Protein Degradation for Cancer Therapy","volume":"25","author":"Hinterndorfer M.","year":"2025","journal-title":"Nature Reviews Cancer"},{"key":"e_1_2_8_3_1","doi-asserted-by":"crossref","first-page":"9582","DOI":"10.1039\/D4CS00411F","article-title":"Proteolysis\u2010Targeting Drug Delivery System (ProDDS): Integrating Targeted Protein Degradation Concepts Into Formulation Design","volume":"53","author":"Chen Y.","year":"2024","journal-title":"Chemical Society Reviews"},{"key":"e_1_2_8_4_1","doi-asserted-by":"crossref","DOI":"10.1002\/anie.202507702","article-title":"Unconventional PROTACs for Targeted Protein Degradation in Cancer Therapy","volume":"64","author":"Zhang X.","year":"2025","journal-title":"Angewandte Chemie International Edition"},{"key":"e_1_2_8_5_1","doi-asserted-by":"crossref","DOI":"10.1002\/adma.202208553","article-title":"Checkpoint Nano\u2010PROTACs for Activatable Cancer Photo\u2010Immunotherapy","volume":"35","author":"Zhang C.","year":"2023","journal-title":"Advanced Materials"},{"key":"e_1_2_8_6_1","doi-asserted-by":"crossref","DOI":"10.1002\/anie.202508538","article-title":"Chemical Proteomics Identifies RBBP7 as a New E3 Ligase Supporting Targeted Protein Degradation","volume":"64","author":"Liu Y.","year":"2025","journal-title":"Angewandte Chemie International Edition"},{"key":"e_1_2_8_7_1","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/j.chembiol.2021.05.010","article-title":"Optical Control of Targeted Protein Degradation","volume":"28","author":"Reynders M.","year":"2021","journal-title":"Cell Chemical Biology"},{"key":"e_1_2_8_8_1","doi-asserted-by":"crossref","first-page":"34669","DOI":"10.1021\/jacs.4c13022","article-title":"Sonodynamic Nano\u2010LYTACs Reverse Tumor Immunosuppressive Microenvironment for Cancer Immunotherapy","volume":"146","author":"Xu M.","year":"2024","journal-title":"Journal of the American Chemical Society"},{"key":"e_1_2_8_9_1","doi-asserted-by":"crossref","first-page":"16377","DOI":"10.1021\/jacs.1c08521","article-title":"Covalently Engineered Nanobody Chimeras for Targeted Membrane Protein Degradation","volume":"143","author":"Zhang H.","year":"2021","journal-title":"Journal of the American Chemical Society"},{"key":"e_1_2_8_10_1","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1080\/15548627.2022.2091338","article-title":"Targeted Protein Degradation via the Autophagy\u2010Lysosome System: AUTOTAC (AUTOphagy\u2010TArgeting Chimera)","volume":"18","author":"Ji C. 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X.","year":"2024","journal-title":"Journal of Medicinal Chemistry"},{"key":"e_1_2_8_36_1","doi-asserted-by":"crossref","DOI":"10.1002\/adfm.202408594","article-title":"Two\u2010Photon Mediated Cancer Therapy: A Comprehensive Review on Two\u2010Photon Photodynamic Therapy and Two\u2010Photon\u2010Activated Therapeutic Delivery Systems","volume":"34","author":"Soleimany A.","year":"2024","journal-title":"Advanced Functional Materials"},{"key":"e_1_2_8_37_1","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.2174\/0113894501269090231012090351","article-title":"BRD4 Protein as a Target for Lung Cancer and Hematological Cancer Therapy: A Review","volume":"24","author":"Zhang M.","year":"2023","journal-title":"Current Drug Targets"},{"key":"e_1_2_8_38_1","doi-asserted-by":"crossref","first-page":"304","DOI":"10.2174\/2210303113666230622123933","article-title":"In\u2010vitro Safety Assessment of Ultrasmall Gold Nanoparticles for Preclinical Drug Delivery Applications","volume":"13","author":"Naz F.","year":"2023","journal-title":"Drug Delivery Letters"},{"key":"e_1_2_8_39_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41571-022-00699-x","article-title":"Targeting Drugs to Tumours Using Cell Membrane\u2010Coated Nanoparticles","volume":"20","author":"Fang R. 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