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Hence, targeting neighboring tumor endothelial cells via the upregulated marker integrin\n                    <jats:italic>\u03b1<\/jats:italic>\n                    V\n                    <jats:italic>\u03b2<\/jats:italic>\n                    3 is a promising strategy. Orthosteric arginine\u2013glycine\u2013aspartate (RGD) ligands of\n                    <jats:italic>\u03b1<\/jats:italic>\n                    V\n                    <jats:italic>\u03b2<\/jats:italic>\n                    3 achieve high affinities but suffer from cross\u2010reactivity. Alternatively, selective targeting of\n                    <jats:italic>\u03b1<\/jats:italic>\n                    V\n                    <jats:italic>\u03b2<\/jats:italic>\n                    3 could potentially be achieved via low\u2010affinity ligands, displayed multivalently on nanoparticles to leverage avidity. To avoid orthosteric site competition, we performed a fragment screening under RGD saturation. Structure\u2013activity relationship (SAR) analysis of the initial hit revealed its binding motif, a 4\u2010methylpyrimidine\u20102\u2010amine core and a conjugation\u2010tolerant position for linker attachment. Multivalent display of the lead compound on liposomes and lipid nanoparticles (LNPs) led to time\u2010, dose\u2010, and valency\u2010dependent uptake in\n                    <jats:italic>\u03b1<\/jats:italic>\n                    V\n                    <jats:italic>\u03b2<\/jats:italic>\n                    3\u2010expressing model cells and in primary human umbilical vein endothelial cells (pHUVECs). In contrast to RGD\u2010decorated NPs, fragment\u2010targeted NPs show superselective behavior (\n                    <jats:italic>\u03b1<\/jats:italic>\n                    <jats:sub>\u03ba<\/jats:sub>\n                    \u22483), that is, a sharp valency\u2010dependent threshold, enabling selective targeting of cells overexpressing\n                    <jats:italic>\u03b1<\/jats:italic>\n                    V\n                    <jats:italic>\u03b2<\/jats:italic>\n                    3. Crucially, mRNA delivered by targeted LNPs translated into functional protein expression six\u2010fold over control. To our knowledge, these findings present the first non\u2010orthosteric, exogenous small\u2010molecule ligands for\n                    <jats:italic>\u03b1<\/jats:italic>\n                    V\n                    <jats:italic>\u03b2<\/jats:italic>\n                    3 and outline their application as a multivalent, superselective delivery platform.\n                  <\/jats:p>","DOI":"10.1002\/anie.1554405","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T17:11:07Z","timestamp":1781802667000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Secondary Site Ligand for Integrin\n                    <i>\u03b1<\/i>\n                    V\n                    <i>\u03b2<\/i>\n                    3 Enables Targeted mRNA Delivery"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6522-2208","authenticated-orcid":false,"given":"Sebastian","family":"Bayer","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Vienna  Vienna Austria"},{"name":"Vienna Doctoral School of Pharmaceutical Nutritional and Sport Sciences University of Vienna  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1648-8659","authenticated-orcid":false,"given":"Mar\u00eda","family":"Garc\u00eda\u2010Garc\u00eda","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1945-2736","authenticated-orcid":false,"given":"Raffaele","family":"Senatore","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4838-7473","authenticated-orcid":false,"given":"Maria","family":"Stratoudaki","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2726-7616","authenticated-orcid":false,"given":"Alina","family":"Markhof","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Vienna  Vienna Austria"},{"name":"Vienna Doctoral School of Pharmaceutical Nutritional and Sport Sciences University of Vienna  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Berger\u2010Becvar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7888-8582","authenticated-orcid":false,"given":"Anna Sophia","family":"Parianou","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Vienna  Vienna Austria"},{"name":"Vienna Doctoral School of Pharmaceutical Nutritional and Sport Sciences University of Vienna  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7082-7239","authenticated-orcid":false,"given":"Christoph","family":"Rademacher","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Vienna  Vienna Austria"},{"name":"Department of Microbiology Immunology and Genetics Max F. 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