{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T02:30:51Z","timestamp":1792549851957,"version":"4.5.0"},"reference-count":39,"publisher":"American Chemical Society (ACS)","issue":"37","license":[{"start":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T00:00:00Z","timestamp":1725840000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T00:00:00Z","timestamp":1725840000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T00:00:00Z","timestamp":1725840000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100001906","name":"Washington Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001906","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32CA080416"],"award-info":[{"award-number":["T32CA080416"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM138036"],"award-info":[{"award-number":["R35GM138036"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000078","name":"Division of Materials Research","doi-asserted-by":"publisher","award":["DMR 1652141"],"award-info":[{"award-number":["DMR 1652141"]}],"id":[{"id":"10.13039\/100000078","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000078","name":"Division of Materials Research","doi-asserted-by":"publisher","award":["DMR 1807398"],"award-info":[{"award-number":["DMR 1807398"]}],"id":[{"id":"10.13039\/100000078","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,9,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Phototriggered release of various cargos, including soluble protein factors and small molecules, has the potential to correct aberrant biological events by offering spatiotemporal control over local therapeutic levels. However, the poor penetration depth of light historically limits implementation to subdermal regions, necessitating alternative methods of light delivery to achieve the full potential of photodynamic therapeutic release. Here, we introduce a strategy exploiting bioluminescence resonance energy transfer (BRET)\u2013an energy transfer process between light-emitting Nanoluciferase (NLuc) and a photosensitive acceptor molecule\u2013to drive biomolecule release from hydrogel biomaterials. Through a facile, one-pot, and high-yielding synthesis (60\u201370%), we synthesized a heterobifunctional ruthenium cross-linker bearing an aldehyde and an azide (CHO-Ru-N3), a compound that we demonstrate undergoes predictable exchange of the azide-bearing ligand under blue-green light irradiation (&amp;gt;550 nm). Following site-specific conjugation to NLuc via sortase-tag enhanced protein ligation (STEPL), the modified protein was covalently attached to a poly(ethylene glycol) (PEG)-based hydrogel via strain-promoted azide\u2013alkyne cycloaddition (SPAAC). Leveraging the high photosensitivity of Ru compounds, we demonstrate rapid and equivalent release of epidermal growth factor (EGF) via either direct illumination or via BRET-based bioluminolysis. As NLuc-originated luminescence can be controlled equivalently throughout the body, we anticipate that this unique protein release strategy will find use for locally triggered drug delivery following systemic administration of a small molecule.<\/jats:p>","DOI":"10.1021\/jacs.4c03361","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T17:22:11Z","timestamp":1725902531000},"page":"25397-25402","source":"Crossref","is-referenced-by-count":17,"title":["Bioluminescence Resonance\nEnergy Transfer (BRET)-Mediated\nProtein Release from Self-Illuminating Photoresponsive Biomaterials"],"prefix":"10.1021","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4775-7604","authenticated-orcid":true,"given":"Teresa L.","family":"Rapp","sequence":"first","affiliation":[{"name":"University of Washington , , , ,","place":["Seattle, Washington, United States, 98105"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3740-6971","authenticated-orcid":true,"given":"Irina","family":"Kopyeva","sequence":"additional","affiliation":[{"name":"University of Washington , , , ,","place":["Seattle, Washington, United States, 98105"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4889-8312","authenticated-orcid":true,"given":"Abhinav","family":"Adhikari","sequence":"additional","affiliation":[{"name":"University of Washington , , , ,","place":["Seattle, Washington, United States, 98105"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0337-3577","authenticated-orcid":true,"given":"Cole A.","family":"DeForest","sequence":"additional","affiliation":[{"name":"University of Washington , , , ,","place":["Seattle, Washington, United States, 98105"]},{"name":"University of Washington , , , ,","place":["Seattle, Washington, United States, 98105"]},{"name":"University of Washington , , , ,","place":["Seattle, Washington, United States, 98105"]},{"name":"University of Washington , , , ,","place":["Seattle, Washington, United States, 98105"]},{"name":"University of Washington , , , ,","place":["Seattle, Washington, United States, 98109"]},{"name":"University of Washington , , , ,","place":["Seattle, Washington, United States, 98105"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2024,9,9]]},"reference":[{"key":"2026101614064037500_cit1","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1146\/annurev-bioeng-060418-052324","article-title":"Programming Stimuli-Responsive Behavior into Biomaterials","volume":"21","author":"Badeau","year":"2019","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"2026101614064037500_cit2","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1016\/j.jconrel.2020.09.044","article-title":"Acetal Containing Polymers as pH-Responsive\nNano-Drug\nDelivery Systems","volume":"328","author":"Gannimani","year":"2020","journal-title":"J. Controlled Release"},{"issue":"32","key":"2026101614064037500_cit3","doi-asserted-by":"publisher","first-page":"1900795","DOI":"10.1002\/adma.201900795","article-title":"Engineering\nBiomimetic Platesomes\nfor pH-Responsive Drug Delivery and Enhanced Antitumor Activity","volume":"31","author":"Liu","year":"2019","journal-title":"Adv. Mater."},{"key":"2026101614064037500_cit4","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.jconrel.2019.07.004","article-title":"Enzyme Responsive Drug Delivery Systems in Cancer Treatment","volume":"308","author":"Shahriari","year":"2019","journal-title":"J. Controlled Release"},{"key":"2026101614064037500_cit5","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2019.119292","article-title":"Reactive Oxygen\nSpecies-Responsive Drug Delivery Systems for the Treatment of Neurodegenerative\nDiseases","volume":"217","author":"Ballance","year":"2019","journal-title":"Biomaterials"},{"key":"2026101614064037500_cit6","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2020.120286","article-title":"ROS-Scavenging Hydrogel to Promote\nHealing of Bacteria Infected Diabetic\nWounds","volume":"258","author":"Zhao","year":"2020","journal-title":"Biomaterials"},{"issue":"19","key":"2026101614064037500_cit7","doi-asserted-by":"publisher","first-page":"10950","DOI":"10.1021\/acs.chemrev.0c00077","article-title":"Guiding Lights:\nTissue Bioprinting Using Photoactivated Materials","volume":"120","author":"Lee","year":"2020","journal-title":"Chem. Rev."},{"issue":"13","key":"2026101614064037500_cit8","doi-asserted-by":"publisher","first-page":"2979","DOI":"10.1039\/D0TB02877K","article-title":"Recent Advances in\nThermo-Sensitive Hydrogels for Drug Delivery","volume":"9","author":"Yu","year":"2021","journal-title":"J. Mater. Chem. B"},{"issue":"4","key":"2026101614064037500_cit9","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1007\/s13346-021-00963-0","article-title":"Ultrasound-Responsive\nPolymer-Based\nDrug Delivery Systems","volume":"11","author":"Wei","year":"2021","journal-title":"Drug Delivery Transl.\nRes."},{"issue":"9","key":"2026101614064037500_cit10","doi-asserted-by":"publisher","first-page":"554","DOI":"10.3390\/gels8090554","article-title":"Ultrasound-Induced\nDrug Release from\nStimuli-Responsive Hydrogels","volume":"8","author":"Yeingst","year":"2022","journal-title":"Gels"},{"issue":"7","key":"2026101614064037500_cit11","doi-asserted-by":"publisher","first-page":"1709","DOI":"10.1007\/s10948-021-05932-9","article-title":"Magnetic Nanoparticles\nin Targeted Drug Delivery: A Review","volume":"34","author":"Kianfar","year":"2021","journal-title":"J. Supercond.\nNov. Magn."},{"key":"2026101614064037500_cit12","doi-asserted-by":"publisher","first-page":"17087","DOI":"10.1038\/natrevmats.2017.87","article-title":"Photoresponsive Biomaterials for\nTargeted Drug Delivery\nand 4D Cell Culture","volume":"3","author":"Ruskowitz","year":"2018","journal-title":"Nat. Rev. Mater."},{"issue":"5923","key":"2026101614064037500_cit13","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1126\/science.1169494","article-title":"Photodegradable\nHydrogels for Dynamic Tuning of Physical and Chemical Properties","volume":"324","author":"Kloxin","year":"2009","journal-title":"Science"},{"issue":"12","key":"2026101614064037500_cit14","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1038\/nchem.1174","article-title":"Cytocompatible Click-Based Hydrogels with Dynamically\nTunable Properties through Orthogonal Photoconjugation and Photocleavage\nReactions","volume":"3","author":"DeForest","year":"2011","journal-title":"Nat. Chem."},{"issue":"3","key":"2026101614064037500_cit15","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/nchem.2917","article-title":"Engineered\nModular Biomaterial Logic Gates for Environmentally Triggered Therapeutic\nDelivery","volume":"10","author":"Badeau","year":"2018","journal-title":"Nat. Chem."},{"key":"2026101614064037500_cit16","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1038\/s41563-019-0367-7","article-title":"Bioactive\nSite-Specifically Modified\nProteins for 4D Patterning of Gel Biomaterials","volume":"18","author":"Shadish","year":"2019","journal-title":"Nat. Mater."},{"issue":"39","key":"2026101614064037500_cit17","doi-asserted-by":"publisher","first-page":"15619","DOI":"10.1021\/jacs.9b07239","article-title":"Genetically Encoded Photocleavable\nLinkers for Patterned Protein Release from Biomaterials","volume":"141","author":"Shadish","year":"2019","journal-title":"J. Am. Chem. Soc."},{"issue":"7","key":"2026101614064037500_cit18","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.201901553","article-title":"Visible Light-Responsive\nDynamic Biomaterials: Going\nDeeper and Triggering More","volume":"9","author":"Rapp","year":"2020","journal-title":"Adv. Healthc. Mater."},{"issue":"42","key":"2026101614064037500_cit19","doi-asserted-by":"publisher","first-page":"9851","DOI":"10.1002\/chem.201902088","article-title":"Dynamic Supramolecular\nRuthenium-Based Gels Responsive to Visible\/NIR Light and Heat","volume":"25","author":"Teasdale","year":"2019","journal-title":"Chem.\u2013Eur. J."},{"issue":"50","key":"2026101614064037500_cit20","doi-asserted-by":"publisher","first-page":"15857","DOI":"10.1002\/anie.201707321","article-title":"Metallo-Supramolecular Gels That Are Photocleavable\nwith Visible and Near-Infrared Irradiation","volume":"56","author":"Theis","year":"2017","journal-title":"Angew. Chem., Int. Ed."},{"issue":"50","key":"2026101614064037500_cit21","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202105989","article-title":"Lighting the\nPath: Light Delivery\nStrategies to Activate Photoresponsive Biomaterials In Vivo","volume":"31","author":"Pearson","year":"2021","journal-title":"Adv. Funct. Mater."},{"issue":"45","key":"2026101614064037500_cit22","doi-asserted-by":"publisher","first-page":"16033","DOI":"10.1002\/anie.201907734","article-title":"Luciferase-Induced\nPhotouncaging: Bioluminolysis","volume":"58","author":"Chang","year":"2019","journal-title":"Angew. Chem.,\nInt. Ed."},{"issue":"10","key":"2026101614064037500_cit23","doi-asserted-by":"publisher","first-page":"3665","DOI":"10.1021\/jacs.0c11016","article-title":"Luciferase\nControlled Protein Interactions","volume":"143","author":"Chang","year":"2021","journal-title":"J. Am. Chem.\nSoc."},{"issue":"1","key":"2026101614064037500_cit24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-018-05916-9","article-title":"Luciferase-Induced\nPhotoreductive Uncaging of Small-Molecule Effectors","volume":"9","author":"Lindberg","year":"2018","journal-title":"Nat. Commun. 2018 91"},{"key":"2026101614064037500_cit25","doi-asserted-by":"publisher","first-page":"2205461","DOI":"10.1002\/smll.202205461","article-title":"Amphiphilic\nMetallodrug\nAssemblies with Red-Light-Enhanced Cellular Internalization and Tumor\nPenetration for Anticancer Phototherapy","volume":"18","author":"Zeng","year":"2022","journal-title":"Small"},{"issue":"35","key":"2026101614064037500_cit26","doi-asserted-by":"publisher","first-page":"3611","DOI":"10.1002\/ejic.202100468","article-title":"Biological\nInvestigations of Ru(II) Complexes with Diverse \u03b2-Diketone Ligands","volume":"2021","author":"Ryan","year":"2021","journal-title":"Eur. J. Inorg. Chem."},{"issue":"1","key":"2026101614064037500_cit27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-022-31269-5","article-title":"Ru(II)\nPhotocages Enable Precise Control over Enzyme Activity with Red Light","volume":"13","author":"Havrylyuk","year":"2022","journal-title":"Nat. Commun."},{"issue":"43","key":"2026101614064037500_cit28","doi-asserted-by":"publisher","first-page":"23397","DOI":"10.1021\/jacs.3c01135","article-title":"Ruthenium-Based\nPhotoactivated Chemotherapy","volume":"145","author":"Bonnet","year":"2023","journal-title":"J. Am. Chem. Soc."},{"key":"2026101614064037500_cit29","doi-asserted-by":"publisher","first-page":"e202316425","DOI":"10.1002\/anie.202316425","article-title":"Red-Light Activation\nof a Microtubule Polymerization Inhibitor via Amide Functionalization\nof the Ruthenium Photocage","volume":"63","author":"Bretin","year":"2024","journal-title":"Angew. Chem., Int.\nEd."},{"issue":"17","key":"2026101614064037500_cit30","doi-asserted-by":"publisher","first-page":"7973","DOI":"10.1021\/acs.inorgchem.4c01008","article-title":"Ruthenium-Cathepsin\nInhibitor Conjugates for Green Light-Activated Photodynamic Therapy\nand Photochemotherapy","volume":"63","author":"Denison","year":"2024","journal-title":"Inorg. Chem."},{"issue":"19","key":"2026101614064037500_cit31","doi-asserted-by":"publisher","first-page":"13317","DOI":"10.1021\/jacs.4c01720","article-title":"RuBi-Ruxolitinib: A Photoreleasable Antitumor JAK Inhibitor","volume":"146","author":"Rafic","year":"2024","journal-title":"J. Am. Chem. Soc."},{"issue":"1","key":"2026101614064037500_cit32","doi-asserted-by":"publisher","first-page":"5250","DOI":"10.1038\/s41467-023-40805-w","article-title":"Tricolor Visible\nWavelength-Selective Photodegradable\nHydrogel Biomaterials","volume":"14","author":"Rapp","year":"2023","journal-title":"Nat. Commun."},{"issue":"9","key":"2026101614064037500_cit33","doi-asserted-by":"publisher","first-page":"4942","DOI":"10.1039\/C8RA09764J","article-title":"Designing\nPhotolabile Ruthenium Polypyridyl Crosslinkers for Hydrogel Formation\nand Multiplexed, Visible-Light Degradation","volume":"9","author":"Rapp","year":"2019","journal-title":"RSC Adv."},{"issue":"10","key":"2026101614064037500_cit34","doi-asserted-by":"publisher","first-page":"2328","DOI":"10.1002\/chem.201704580","article-title":"Ruthenium-Crosslinked\nHydrogels with Rapid","volume":"24","author":"Rapp","year":"2018","journal-title":"Visible-Light Degradation.\nChem. - Eur. J."},{"issue":"January","key":"2026101614064037500_cit35","doi-asserted-by":"publisher","first-page":"2342","DOI":"10.1039\/C4SC03990D","article-title":"Ruthenium-Caged\nAntisense Morpholinos for Regulating Gene Expression in Zebrafish\nEmbryos","volume":"6","author":"Griepenburg","year":"2015","journal-title":"Chem. Sci."},{"issue":"9","key":"2026101614064037500_cit36","doi-asserted-by":"publisher","first-page":"2670","DOI":"10.1021\/ja039915e","article-title":"Sortase-Mediated\nProtein Ligation: A New Method for Protein Engineering","volume":"126","author":"Mao","year":"2004","journal-title":"J. Am. Chem. Soc."},{"issue":"1","key":"2026101614064037500_cit37","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.matt.2019.11.011","article-title":"Site-Selective Protein\nModification: From Functionalized\nProteins to Functional Biomaterials","volume":"2","author":"Shadish","year":"2020","journal-title":"Matter"},{"issue":"22","key":"2026101614064037500_cit38","doi-asserted-by":"publisher","first-page":"11090","DOI":"10.1021\/ac402871k","article-title":"Sortase-Tag Expressed\nProtein Ligation: Combining Protein Purification and Site-Specific\nBioconjugation into a Single Step","volume":"85","author":"Warden-Rothman","year":"2013","journal-title":"Anal. Chem."},{"key":"2026101614064037500_cit39","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1038\/s41596-023-00938-0","article-title":"Irreversible\nLight-Activated SpyLigation Mediates Split-Protein\nAssembly in 4D","volume":"19","author":"Munoz-Robles","year":"2024","journal-title":"Nat. Protoc."}],"container-title":["Journal of the American\nChemical Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jacs.4c03361","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/146\/37\/25397\/68892693\/jacs.4c03361.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/146\/37\/25397\/68892693\/jacs.4c03361.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:49:17Z","timestamp":1792176557000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jacsat\/article\/146\/37\/25397\/157676\/Bioluminescence-Resonance-Energy-Transfer-BRET"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,9]]},"references-count":39,"journal-issue":{"issue":"37","published-online":{"date-parts":[[2024,9,9]]},"published-print":{"date-parts":[[2024,9,18]]}},"URL":"https:\/\/doi.org\/10.1021\/jacs.4c03361","relation":{},"ISSN":["0002-7863","1520-5126"],"issn-type":[{"value":"0002-7863","type":"print"},{"value":"1520-5126","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,9]]}}}