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The final structural outcome is not only determined by the system's composition but also depends on the details and kinetics of the pathway chosen to navigate the energetic landscape during the assembly process. In this study, a distinct manifestation of pathway complexity is presented in the formation of short double\u2010stranded DNA (dsDNA)\u2010loaded polyion complex (PIC) micelles. Besides the conventional assembly pathway of rapidly mixing dsDNA with preformed polycationic block copolymers, compositionally equivalent PIC micelles are prepared via polymerization\u2010induced electrostatic self\u2010assembly (PIESA). A combination of synchrotron time\u2010resolved small\u2010angle x\u2010ray scattering (TR\u2010SAXS), cryogenic transmission electron microscopy (cryo\u2010TEM), and fluorescence correlation spectroscopy (FCS) reveals the formation of spheroidal particles during direct mixing, whereas PIESA generates hexagonal disk\u2010shaped colloids with internal crystalline dsDNA ordering. A molecular assembly mechanism for PIESA is postulated, which relies on the continuous formation of charge\u2010neutralized complexes that act as primary building blocks for the colloidal hexagons. Mechanistic insights into pathway complexity during PIC micellization establish assembly pathway control as a strategy to tune the particle's physicochemical properties beyond conventional design parameters, such as polymer size and chemistry. This approache expands the opportunities for therapeutic oligonucleotide delivery through control over morphology and cargo loading.<\/jats:p>","DOI":"10.1002\/anie.9345533","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T05:48:36Z","timestamp":1789105716000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pathway Complexity Defines the Shape of Nucleic Acid\u2010Loaded Polyion Complex Micelles: Spheroids vs. Hexagonal Disks"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0836-4452","authenticated-orcid":false,"given":"Lennart","family":"van den Hoven","sequence":"first","affiliation":[{"name":"Division of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences Faculty of Science Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2761-6449","authenticated-orcid":false,"given":"Neshat","family":"Moslehi","sequence":"additional","affiliation":[{"name":"Laboratory of Self\u2010Organizing Soft Matter Department of Chemical Engineering and Chemistry &amp; Institute For Complex Molecular Systems Eindhoven University of Technology  Eindhoven The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3345-4223","authenticated-orcid":false,"given":"Eline F.","family":"Brink","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences Faculty of Science Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6326-1951","authenticated-orcid":false,"given":"Austin","family":"Hubley","sequence":"additional","affiliation":[{"name":"European Synchrotron Radiation Facility (ESRF)  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3543-4821","authenticated-orcid":false,"given":"Ilja K.","family":"Voets","sequence":"additional","affiliation":[{"name":"Laboratory of Self\u2010Organizing Soft Matter Department of Chemical Engineering and Chemistry &amp; Institute For Complex Molecular Systems Eindhoven University of Technology  Eindhoven The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6047-5900","authenticated-orcid":false,"given":"Tina","family":"Vermonden","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences Faculty of Science Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2508-7478","authenticated-orcid":false,"given":"Elham","family":"Mirzahossein","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences Faculty of Science Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9024-3927","authenticated-orcid":false,"given":"Bas G. 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