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Current state-of-the-art genetically engineered mouse models often rely on viral delivery of recombinases, such as Cre recombinase, to initiate transformation. However, viral particles can infect and activate innate immune cells, thus potentially impacting studies of tumor-immune dynamics. Here, we develop a layer-by-layer (LbL) polyplex platform using poly(\u03b2-aminoester) (PBAE) polymers layered with poly-L-aspartic acid (PLD) to deliver Cre mRNA to lungs while avoiding immune cell transfection and activation. PLD-coated nanoparticles (PLD-NPs) exhibit stable mRNA encapsulation and efficient transfection in vitro, even after lyophilization and long-term storage. In Kras\n                  <jats:sup>LSL-G12D\/+<\/jats:sup>\n                  ;p53\n                  <jats:sup>flox\/flox<\/jats:sup>\n                  (KP) mice, PLD-NPs initiate lung adenocarcinomas that mirror human histopathology without infecting or activating dendritic cells and alveolar macrophages, unlike lentiviral (LV) or adenoviral delivery methods. Single-cell transcriptional profiling revealed that LV administration drives long-term upregulation of antigen presentation and costimulatory machinery in lung-resident myeloid populations. This persistent immune activation is avoided by NP delivery. By uncoupling tumor initiation from innate immune activation, this platform enables the high-fidelity interrogation of tumor-immune dynamics, especially for non-inflammation-driven lung cancer.\n                <\/jats:p>","DOI":"10.64898\/2026.09.14.751530","type":"posted-content","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T04:10:13Z","timestamp":1789963813000},"source":"Crossref","is-referenced-by-count":0,"title":["Modeling lung adenocarcinoma using layer-by-layer nanoparticles mitigates innate immune cell activation"],"prefix":"10.64898","author":[{"given":"Vidit","family":"Bhandarkar","sequence":"first","affiliation":[{"name":"Department of Biology at MIT"},{"name":"Koch Institute for Integrative Cancer Research at MIT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elen","family":"Torres-Mejia","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research at MIT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor A.","family":"Heim","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research at MIT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namita","family":"Nabar","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research at MIT"},{"name":"Department of Chemical Engineering at MIT"},{"name":"Broad Institute of MIT and Harvard"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara G.","family":"Dacoba","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research at MIT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary J.","family":"Rogers","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research at MIT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Mathey-Andrews","sequence":"additional","affiliation":[{"name":"Department of Biology at MIT"},{"name":"Koch Institute for Integrative Cancer Research at MIT"},{"name":"4Harvard Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean-Luc","family":"Shanahan","sequence":"additional","affiliation":[{"name":"Department of Biology at MIT"},{"name":"Koch Institute for Integrative Cancer Research at MIT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chau","family":"Vo","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research at MIT"},{"name":"Program in Health Sciences and Technology at Harvard and MIT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Berger","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research at MIT"},{"name":"4Harvard Medical School"},{"name":"Program in Health Sciences and Technology at Harvard and MIT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0921-3144","authenticated-orcid":false,"given":"J. 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