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Unlike drug\u2010eluting stents (DES), DCBs must achieve meaningful drug transfer, penetration, and retention during a single, brief inflation. This review provides a mechanistic, bench\u2010to\u2010bedside framework linking drug physicochemistry, excipient chemistry, coating engineering, balloon mechanics, and tissue pharmacokinetics to angiographic and clinical outcomes. Paclitaxel\u2010based DCBs consistently outperform sirolimus\u2010coated platforms in early drug uptake, intracellular retention, transmural distribution, and late lumen loss. These advantages derive from paclitaxel's extreme lipophilicity, particulate deposition, and high\u2010affinity microtubule binding, which enable durable antiproliferative activity despite modest absolute transfer. Sirolimus, by contrast, requires an engineered delivery system\u2014crystalline matrices, PLGA micro\u2010reservoirs, nanoparticle carriers, or pressure\u2010driven infusion\u2014to compensate for its lower membrane permeability and reversible intracellular binding. Integrating preclinical modeling, coating\u2010stability studies, optical coherence tomography (OCT) remodeling signatures, randomized trials, and recent meta\u2010analyses, this review demonstrates that DCB therapy is not a drug\u2010class effect: technology, not drug load, determines biological behavior. Early transfer efficiency, tissue retention kinetics, depth of penetration, and platform\u2010specific dissection response fully explain the divergent angiographic patterns observed across devices. Understanding these mechanistic principles is essential for rational device selection and for guiding the next generation of DCB technologies capable of achieving consistent and durable clinical performance.<\/jats:p>","DOI":"10.1002\/ccd.70542","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T17:25:12Z","timestamp":1772990712000},"page":"1796-1807","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Drug\u2010Coated Balloons in Coronary Artery Disease: Engineering, Pharmacology, and the Mechanisms Behind Angiographic Outcomes"],"prefix":"10.1002","volume":"107","author":[{"given":"Marcello","family":"Marchetta","sequence":"first","affiliation":[{"name":"Department of Biomedicine and Prevention Tor Vergata University Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Paragliola","sequence":"additional","affiliation":[{"name":"Department 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