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Numerous studies have investigated the impact of size, shape, charge, and surface functionality of nanoparticles on mammalian cellular uptake. Rigidity has been studied to a far lesser extent, and its effects are still unclear. Here, the importance of this property, and its interplay with particle size, is systematically explored using a library of core\u2010shell spherical PEGylated nanoparticles synthesized by RAFT emulsion polymerization. Rigidity of these particles is controlled by altering the intrinsic glass transition temperature of their constituting polymers. Three polymeric core rigidities are tested: hard, medium, and soft using two particle sizes, 50 and 100\u2009nm diameters. Cellular uptake studies indicate that softer particles are taken up faster and threefold more than harder nanoparticles with the larger 100\u2009nm particles. In addition, the study indicates major differences in the cellular uptake pathway, with harder particles being internalized through clathrin\u2010 and caveolae\u2010mediated endocytosis as well as macropinocytosis, while softer particles are taken up bycaveolae\u2010 and non\u2010receptormediated endocytosis. However, 50 nm derivatives do not show any appreciable differences in uptake efficiency, suggesting that rigidity as a parameter in the biological regime may be size dependent.<\/jats:p>","DOI":"10.1002\/smll.202203070","type":"journal-article","created":{"date-parts":[[2022,8,20]],"date-time":"2022-08-20T03:35:20Z","timestamp":1660966520000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["Probing the Effect of Rigidity on the Cellular Uptake of Core\u2010Shell Nanoparticles: Stiffness Effects are Size Dependent"],"prefix":"10.1002","volume":"18","author":[{"given":"Pratik","family":"Gurnani","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Warwick  Gibbet Hill Road Coventry CV4 7AL UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9522-0019","authenticated-orcid":false,"given":"Carlos","family":"Sanchez\u2010Cano","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Warwick  Gibbet Hill Road Coventry CV4 7AL UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Xandri\u2010Monje","sequence":"additional","affiliation":[{"name":"Warwick Medical School University of Warwick  Gibbet Hill Road Coventry CV4 7AL UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junliang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Warwick  Gibbet Hill Road Coventry CV4 7AL UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean H.","family":"Ellacott","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Warwick  Gibbet Hill Road Coventry CV4 7AL UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward D. 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