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PEGylated nanoparticles mitigate these interactions by forming a protective steric layer on their surfaces. However, there is a lack of a predictive tool that gives mechanistic insights about how PEG surface density governs the underlying interaction and results in enhanced diffusive transport of LNPs through the ECM. Here, we present a multi-scale hierarchical computational framework that couples all-atom constant pH molecular dynamics (CpHMD) with a highly coarse-grained model of the complete LNP within a crosslinked hyaluronic acid (HA) network. These atomistic simulations resolve the free energy of interaction between the LNP surface and HA chains across varying PEG lipid compositions, and integrate these free energy profiles to inform the coarse-grained simulations of LNP transport through the matrix. This work highlights that even a slightly PEGylated surface depletes the near-contact shell between the LNP and HA chains, which disrupts their adhesive interactions. These protective PEG layers produce a sharp, non-linear enhancement in LNP diffusivities, with just 1% PEG increasing the diffusivity nearly eight-fold relative to bare LNPs, which remain trapped in the matrix structures. This work provides a quantitative estimate of how PEG surface density governs LNP transport through the ECM, which offers predictive guidance for engineering LNP surface properties in target-specific drug delivery.<\/jats:p>","DOI":"10.64898\/2026.09.09.750406","type":"posted-content","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:25:12Z","timestamp":1789071912000},"source":"Crossref","is-referenced-by-count":0,"title":["A multiscale modeling framework for transport of PEGylated lipid nanoparticle through the extracellular matrix"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7962-3328","authenticated-orcid":false,"given":"Prasheel","family":"Nakate","sequence":"first","affiliation":[{"name":"School of Mechanical Engineering, Purdue University, West Lafayette, Indiana 47907, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle J.","family":"Colston","sequence":"additional","affiliation":[{"name":"Department of Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, Indiana 47907, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9511-9922","authenticated-orcid":false,"given":"Severin T.","family":"Schneebeli","sequence":"additional","affiliation":[{"name":"Department of Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, Indiana 47907, United States"},{"name":"James Tarpo Jr. and Margo Tarpo Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3301-3193","authenticated-orcid":false,"given":"Arezoo M.","family":"Ardekani","sequence":"additional","affiliation":[{"name":"School of Mechanical Engineering, Purdue University, West Lafayette, Indiana 47907, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091302000863000_2026.09.09.750406v1.1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.addr.2018.07.008","volume":"130","year":"2018","journal-title":"Advanced drug delivery reviews"},{"key":"2026091302000863000_2026.09.09.750406v1.2","doi-asserted-by":"crossref","first-page":"2001812","DOI":"10.1002\/adhm.202001812","volume":"10","year":"2021","journal-title":"Advanced healthcare materials"},{"key":"2026091302000863000_2026.09.09.750406v1.3","doi-asserted-by":"crossref","first-page":"119680","DOI":"10.1016\/j.biomaterials.2019.119680","volume":"231","year":"2020","journal-title":"Biomaterials"},{"key":"2026091302000863000_2026.09.09.750406v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2019.05.030"},{"key":"2026091302000863000_2026.09.09.750406v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2020.04.012"},{"key":"2026091302000863000_2026.09.09.750406v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2016.01.005"},{"key":"2026091302000863000_2026.09.09.750406v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2005.10.010"},{"key":"2026091302000863000_2026.09.09.750406v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpb.2016.08.007"},{"key":"2026091302000863000_2026.09.09.750406v1.9","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.4c10381"},{"key":"2026091302000863000_2026.09.09.750406v1.10","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1021\/mp200626j","volume":"9","year":"2012","journal-title":"Molecular pharmaceutics"},{"key":"2026091302000863000_2026.09.09.750406v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/nmat2442"},{"key":"2026091302000863000_2026.09.09.750406v1.12","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.jconrel.2010.03.016","volume":"145","year":"2010","journal-title":"Journal of Controlled Release"},{"key":"2026091302000863000_2026.09.09.750406v1.13","doi-asserted-by":"crossref","first-page":"5304","DOI":"10.1021\/nl302638g","volume":"12","year":"2012","journal-title":"Nano letters"},{"key":"2026091302000863000_2026.09.09.750406v1.14","doi-asserted-by":"crossref","unstructured":"S. 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