{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T15:57:50Z","timestamp":1783353470139,"version":"3.54.6"},"reference-count":38,"publisher":"Wiley","issue":"47","license":[{"start":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T00:00:00Z","timestamp":1690243200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T00:00:00Z","timestamp":1690243200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172086"],"award-info":[{"award-number":["82172086"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013806","name":"Shenyang Pharmaceutical University","doi-asserted-by":"publisher","award":["ZQN2019004"],"award-info":[{"award-number":["ZQN2019004"]}],"id":[{"id":"10.13039\/501100013806","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["CSC202207960005"],"award-info":[{"award-number":["CSC202207960005"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["CSC202107960001"],"award-info":[{"award-number":["CSC202107960001"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Small"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Methicillin\u2010resistant\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    (MRSA) biofilm\u2010associated bacterial keratitis is highly intractable, with strong resistance to \u03b2\u2010lactam antibiotics. Inhibiting the MRSA resistance gene mecR1 to downregulate penicillin\u2010binding protein PBP2a has been implicated in the sensitization of \u03b2\u2010lactam antibiotics to MRSA. However, oligonucleotide gene regulators struggle to penetrate dense biofilms, let alone achieve efficient gene regulation inside bacteria cells. Herein, an eye\u2010drop system capable of penetrating biofilms and targeting bacteria for chemo\u2010gene therapy in MRSA\u2010caused bacterial keratitis is developed. This system employed rolling circle amplification to prepare DNA nanoflowers (DNFs) encoding MRSA\u2010specific aptamers and mecR1 deoxyribozymes (DNAzymes). Subsequently, \u03b2\u2010lactam antibiotic ampicillin (Amp) and zinc oxide (ZnO) nanoparticles are sequentially loaded into the DNFs (ZnO\/Amp@DNFs). Upon application, ZnO on the surface of the nanosystem disrupts the dense structure of biofilm and fully exposes free bacteria. Later, bearing encoded aptamer, the nanoflower system is intensively endocytosed by bacteria, and releases DNAzyme under acidic conditions to cleave the mecR1 gene for PBP2a down\u2010regulation, and ampicillin for efficient MRSA elimination. In vivo tests showed that the system effectively cleared bacterial and biofilm in the cornea, suppressed proinflammatory cytokines interleukin 1\u03b2 \uff08IL\u20101\u03b2\uff09 and tumor neocrosis factor\u2010alpha \uff08TNF\u2010\u03b1\uff09, and is safe for corneal epithelial cells. Overall, this design offers a promising approach for treating MRSA\u2010induced keratitis.\n                  <\/jats:p>","DOI":"10.1002\/smll.202304194","type":"journal-article","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T13:57:12Z","timestamp":1690293432000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["DNA Nanoflower Eye Drops with Antibiotic\u2010Resistant Gene Regulation Ability for MRSA Keratitis Target Treatment"],"prefix":"10.1002","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3763-7960","authenticated-orcid":false,"given":"Meixin","family":"Ran","sequence":"first","affiliation":[{"name":"Joint Centre of Translational Medicine The First Affiliated Hospital of Wenzhou Medical University  Wenzhou, Zhejiang Province 325015 China"},{"name":"Pharmaceutical Sciences Laboratory \u00c5bo Akademi University Turku Bioscience Centre University of Turku and \u00c5bo Akademi University  Turku 20520 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics School of Pharmacy Shenyang Pharmaceutical University Shenyang  Shenyang 110016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Yan","sequence":"additional","affiliation":[{"name":"Joint Centre of Translational Medicine The First Affiliated Hospital of Wenzhou Medical University  Wenzhou, Zhejiang Province 325015 China"},{"name":"Pharmaceutical Sciences Laboratory \u00c5bo Akademi University Turku Bioscience Centre University of Turku and \u00c5bo Akademi University  Turku 20520 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arto T.","family":"Pulliainen","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine Research Unit for Infection and Immunity University of Turku  Kiinamyllynkatu 10 Turku FI\u201020520 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics School of Pharmacy Shenyang Pharmaceutical University Shenyang  Shenyang 110016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1071-4416","authenticated-orcid":false,"given":"Hongbo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Joint Centre of Translational Medicine The First Affiliated Hospital of Wenzhou Medical University  Wenzhou, Zhejiang Province 325015 China"},{"name":"Pharmaceutical Sciences Laboratory \u00c5bo Akademi University Turku Bioscience Centre University of Turku and \u00c5bo Akademi University  Turku 20520 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,25]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2020.09.014"},{"key":"e_1_2_8_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12274-022-4744-1"},{"key":"e_1_2_8_1_3","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202206437"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.7b01023"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.9b08930"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.5114\/aoms.2011.23404"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.5812\/jjm.9181"},{"key":"e_1_2_8_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12906-015-0699-z"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2BM00640E"},{"key":"e_1_2_8_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2023.114724"},{"key":"e_1_2_8_5_3","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02061-1"},{"key":"e_1_2_8_5_4","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-021-00665-4"},{"key":"e_1_2_8_5_5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2112696119"},{"key":"e_1_2_8_5_6","doi-asserted-by":"publisher","DOI":"10.1039\/D1CS00617G"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmt.2023.01.004"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202300374"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.2007.04705.x"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00294-021-01212-0"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/SMMD.20220015"},{"key":"e_1_2_8_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/SMMD.20220012"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202207787"},{"key":"e_1_2_8_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2016268117"},{"key":"e_1_2_8_11_3","doi-asserted-by":"publisher","DOI":"10.1016\/j.trechm.2021.03.009"},{"key":"e_1_2_8_11_4","doi-asserted-by":"publisher","DOI":"10.1039\/D1CS01148K"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202007738"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.colsurfb.2017.07.056"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.9b01589"},{"key":"e_1_2_8_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202101474"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/app12020710"},{"key":"e_1_2_8_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.compositesb.2020.108415"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2018.09.019"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics10040284"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S121956"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cej.2022.139839"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.nanolett.1c01727"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/nano.202200026"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-146-10-2395"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-18-0873"}],"updated-by":[{"DOI":"10.1002\/smll.202503709","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T00:00:00Z","timestamp":1744848000000}}],"container-title":["Small"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/smll.202304194","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/smll.202304194","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/smll.202304194","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T08:34:07Z","timestamp":1770280447000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/smll.202304194"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,25]]},"references-count":38,"journal-issue":{"issue":"47","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["10.1002\/smll.202304194"],"URL":"https:\/\/doi.org\/10.1002\/smll.202304194","archive":["Portico"],"relation":{},"ISSN":["1613-6810","1613-6829"],"issn-type":[{"value":"1613-6810","type":"print"},{"value":"1613-6829","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,25]]},"assertion":[{"value":"2023-05-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2304194"}}