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However, how assembly solution conditions and polymer molecular weight (MW) govern LbL-NP properties remains poorly understood. We investigated the influence of layering buffer ionic strength and polymer MW on the functional performance of PLR\/PLE bilayer-coated LbL-NPs designed to promote cancer cell targeting and NP retention on the extracellular membrane to deliver the cytokine interleukin-12 (IL-12). Assembly under mild ionic strength conditions increased LbL film stability but reduced IL-12 bioavailability and lipid exchange at the NP surface, ultimately diminishing therapeutic efficacy. In contrast, highly stable LbL-NPs assembled using high-MW (HMW) polymers under low ionic strength conditions exhibited enhanced in vitro NP association, increased cancer cell surface retention, and improved tumor accumulation in vivo in a metastatic ovarian cancer model, leading to improved efficacy and long-term survival. Molecular dynamics (MD) simulations revealed that HMW polymer layering produced denser PLE outer layer architecture compared to more highly interpenetrated LMW layers, providing structural insight into the superior performance of HMW LbL-NPs. These results demonstrate that control over LbL-NP delivery performance is influenced by polymer MW and assembly conditions, with HMW polymers augmenting the performance of PLR\/PLE-coated NPs for IL-12 delivery.<\/jats:p>","DOI":"10.1021\/acsnano.6c02817","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T23:40:52Z","timestamp":1783986052000},"page":"20570-20584","source":"Crossref","is-referenced-by-count":1,"title":["Polymer Molecular\nWeight Influences Cancer Cell Surface\nRetention and Cytokine Presentation by Layer-by-Layer Nanoparticles"],"prefix":"10.1021","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4035-0027","authenticated-orcid":true,"given":"Ivan S.","family":"Pires","sequence":"first","affiliation":[{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]},{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezra","family":"Gordon","sequence":"additional","affiliation":[{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7560-8611","authenticated-orcid":true,"given":"Aidan","family":"Kindopp","sequence":"additional","affiliation":[{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]},{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5662-6542","authenticated-orcid":true,"given":"Alexander D.","family":"Stoneman","sequence":"additional","affiliation":[{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]},{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gil","family":"Covarrubias","sequence":"additional","affiliation":[{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo J.","family":"Esparza","sequence":"additional","affiliation":[{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria F.","family":"Gomerdinger","sequence":"additional","affiliation":[{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]},{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Maiorino","sequence":"additional","affiliation":[{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heikyung","family":"Suh","sequence":"additional","affiliation":[{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrell J.","family":"Irvine","sequence":"additional","affiliation":[{"name":"The Scripps Research Institute , , , ,","place":["La Jolla, California, United States, 92037"]},{"name":"Howard Hughes Medical Institute , , ,","place":["Chevy Chase, Maryland, United States, 20815"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9835-192X","authenticated-orcid":true,"given":"Paula T.","family":"Hammond","sequence":"additional","affiliation":[{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]},{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]},{"name":"Broad Institute of MIT and Harvard , , ,","place":["Cambridge, Massachusetts, United States, 02139"]},{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"issue":"4","key":"2026072810080213300_cit1","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1038\/s41578-020-00269-6","article-title":"Targeted Drug Delivery Strategies for Precision Medicines","volume":"6","author":"Manzari","year":"2021","journal-title":"Nat. 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