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Despite decades of research, the 5\u2010year survival rate is 50%. Strikingly, the overall incidence rate is projected to increase by 30% in the next 10 years, which may result in a sharp increase in mortality. Two fundamental aspects of OSCC are that it progresses via the inactivation and mutation of tumor suppressor genes (TSGs) and has a \u201ccold\u201d tumor microenvironment (TME). A major barrier in the treatment of OSCC is the lack of novel therapies clinicians have at their disposal that are designed to disrupt tumor progression by reshaping the cold tumors into inflammatory \u201chot\u201d tumors. To overcome these obstacles, we employed a lipid nanoparticle (LNP) that co\u2010encapsulates p53 mRNA and the small molecule ciclopirox (CPX). We demonstrate that both drugs have innate chemotherapeutic properties by facilitating caspase activation. Moreover, these therapies can create a less immunosuppressive TME in part by repolarizing tumor\u2010associated macrophages (TAMs) to M1\u2010like phenotypes. When formulated together, our platform provides an all\u2010in\u2010one approach for OSCC, effective in both p53\u2010therapy\u2010susceptible and p53\u2010therapy\u2010resistant models. Additionally, this work offers a template for a delivery platform capable of tackling multiple mechanisms of OSCC progression and survival.<\/jats:p>","DOI":"10.1002\/adma.73721","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T11:49:11Z","timestamp":1784029751000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lipid Nanoparticle Co\u2010Delivery of mRNA and a Small Molecule Drug for Oral Cancer Chemoimmunotherapy"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3607-790X","authenticated-orcid":false,"given":"Marshall S.","family":"Padilla","sequence":"first","affiliation":[{"name":"Department of Bioengineering School of Engineering and Applied Science University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline 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