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Herein, we developed an innovative fentanyl\u2010responsive microneedle (MN) patch (iNal patch) engineered as an autonomous harm reduction tool to dynamically release naloxone on demand in response to fentanyl levels. Specifically, the iNal patch integrates mesoporous silica nanoparticles (MSNs) loaded with naloxone. The nanoparticle surfaces are modified by fentanyl\u2010sensitive aptamers, allowing precise and dose\u2010dependent drug release triggered by fentanyl exposure. The engineered MN matrix composed of swellable maleated poly(vinyl alcohol) facilitates rapid skin penetration and interstitial fluid access, ensuring immediate and sustained naloxone release. From in vitro and in vivo studies, the iNal patch was demonstrated to effectively reverse fentanyl\u2010induced opioid overdose symptoms, rapidly restore normal physiological behaviors in mice, and enable multiple responsive drug\u2010release cycles to prevent renarcotization. This proof\u2010of\u2010concept MN platform establishes a new paradigm for materials\u2010based harm reduction, offering an autonomous safety net for high\u2010risk populations independent of human supervision.<\/jats:p>","DOI":"10.1002\/advs.202524301","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T13:59:44Z","timestamp":1783605584000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Fentanyl\u2010Responsive Microneedle Patch for Harm Reduction"],"prefix":"10.1002","volume":"13","author":[{"given":"Penghui","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Biological Systems Engineering Virginia Tech  Blacksburg Virginia USA"},{"name":"Academy of Integrated Science, College of Science Virginia Tech Blacksburg Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zerui","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Biological Systems Engineering Virginia Tech  Blacksburg Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Wolter","sequence":"additional","affiliation":[{"name":"Academy of Integrated Science, College of Science Virginia Tech Blacksburg Virginia USA"},{"name":"School of Pharmacy University of Wisconsin\u2010Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanqing","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Biological Systems Engineering Virginia Tech  Blacksburg Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanzhi","family":"Bian","sequence":"additional","affiliation":[{"name":"Department of Biological Systems Engineering Virginia Tech  Blacksburg Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chixia","family":"Tian","sequence":"additional","affiliation":[{"name":"Academy of Integrated Science, College of Science Virginia Tech Blacksburg Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Xu","sequence":"additional","affiliation":[{"name":"Sydney Dental School The University of Sydney  Camperdown New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biological Systems Engineering Virginia Tech  Blacksburg Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juhong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of California Riverside  Riverside California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew W.","family":"Buczynski","sequence":"additional","affiliation":[{"name":"School of Neuroscience Virginia Tech  Blacksburg Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3167-111X","authenticated-orcid":false,"given":"Wujin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Biological Systems Engineering Virginia Tech  Blacksburg Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.15620\/cdc:135849"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abm8147"},{"key":"e_1_2_8_4_1","volume-title":"Drug Overdose Mortality by Usual Occupation and Industry: 46 U.S. States and New York City","author":"Billock R. 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