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First\u2010generation microneedle arrays address this issue by penetrating the stratum corneum; however, their passive, diffusion\u2010based release limits delivery depth, kinetics, and adaptability. In this review, we discuss force\u2010driven microneedles (F\u2010MNs) as a shift from passive permeation to active propulsion. F\u2010MNs integrate mechanisms that generate localized physical driving forces to rapidly and controllably drive therapeutic payloads into tissue, achieving millimeter\u2010scale penetration within seconds to minutes. We categorize four principal modalities based on their force\u2010generation mechanism: gas\u2010driven microneedles, cavitation\u2010driven microneedles, magnetically actuated microneedles, and iontophoresis\u2010enhanced microneedles. For each class, underlying mechanisms, material choices, safety considerations, and translational challenges are presented. 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By framing F\u2010MNs around their force\u2010generation mechanisms and translational barriers, this review outlines design rules and clinical application spaces for deep, rapid, and controllable microneedle\u2010mediated therapy across transdermal, mucosal, gastrointestinal, wound, and tumor\u2010related delivery\u00a0settings.<\/jats:p>","DOI":"10.1002\/smll.75300","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:08:09Z","timestamp":1787562489000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Driving Drugs Deeper: Force\u2010Driven Microneedle Systems for Active Therapy and Their Road Towards Clinical Implementation"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1892-2292","authenticated-orcid":false,"given":"Majed","family":"Amini","sequence":"first","affiliation":[{"name":"Department of Electrical and Computer Engineering University of Waterloo Waterloo Ontario Canada"},{"name":"Waterloo Institute for Nanotechnology University of Waterloo Waterloo Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phoebe","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Electrical and Computer Engineering University of Waterloo Waterloo Ontario Canada"},{"name":"Waterloo Institute for Nanotechnology University of Waterloo Waterloo Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1498-5114","authenticated-orcid":false,"given":"Hamed","family":"Shahsavan","sequence":"additional","affiliation":[{"name":"Waterloo Institute for Nanotechnology University of Waterloo Waterloo Ontario Canada"},{"name":"Department of Chemical Engineering University of Waterloo Waterloo Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8684-3102","authenticated-orcid":false,"given":"Mahla","family":"Poudineh","sequence":"additional","affiliation":[{"name":"Department of Electrical and Computer Engineering University of Waterloo Waterloo Ontario Canada"},{"name":"Waterloo Institute for Nanotechnology University of Waterloo Waterloo Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/1567201816666190201143457"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1089\/jamp.2016.1297"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.3132\/pcrj.2007.00017"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41378-025-00970-y"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/archderm.1953.01540110113025"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2024.115301"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1147718"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dza.2010.08.002"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13059"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1504"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1109\/JMEMS.2003.820293"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.201200864"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/js980042"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jddst.2015.05.001"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12247-020-09460-2"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1109\/TBME.2005.845240"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2006.10.017"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2182"},{"issue":"9","key":"e_1_2_13_20_1","first-page":"3114","article-title":"A Dissolving Microneedle Patch Loaded with Zinc Oxide Nanoparticles and H2O2$H_{2}O_{2}$\u2010Responsive Prodrug for H2O2$H_{2}O_{2}$\u2010Driven Gas\u2010Propelling Synergistic Antibacterial Therapy of Subcutaneous Fungal Infection","volume":"11","author":"Zeng Y. 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