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Targeted RNA delivery to lung endothelial cells has the potential to treat conditions that involve inflammation, such as chronic asthma and obstructive pulmonary disease. To this end, chemically modified dendrimer nanomaterials were synthesized and optimized for targeted small interfering RNA (siRNA) delivery to lung vasculature. Using a combinatorial approach, the free amines on multigenerational poly(amido amine) and poly(propylenimine) dendrimers were substituted with alkyl chains of increasing length. The top performing materials from in vivo screens were found to primarily target Tie2-expressing lung endothelial cells. At high doses, the dendrimer–lipid derivatives did not cause chronic increases in proinflammatory cytokines, and animals did not suffer weight loss due to toxicity. We believe these materials have potential as agents for the pulmonary delivery of RNA therapeutics., National Institutes of Health (U.S.) Centers of Cancer and Nanotechnology Excellence (Grant U54 CA151884), Armed Forces Institute of Regenerative Medicine (Grant W81XWH-08-2-0034), Alnylam Pharmaceuticals (Firm), American Association for Cancer Research (Fellowship), Leukemia & Lymphoma Society of America (Fellowship), National Cancer Institute (U.S.) (Grant 1K99CA169512), Juvenile Diabetes Research Fund, American Society for Engineering Education. National Defense Science and Engineering Graduate Fellowship, National Science Foundation (U.S.). Graduate Research Fellowship Program, Massachusetts Institute of Technology. Presidential Fellowship, Mazumdar-Shaw International Oncology Fellowship

MicroRNAs (miRNAs) and siRNAs have enormous potential as cancer therapeutics, but their effective delivery to most solid tumors has been difficult. Here, we show that a new lung-targeting nanoparticle is capable of delivering miRNA mimics and siRNAs to lung adenocarcinoma cells in vitro and to tumors in a genetically engineered mouse model of lung cancer based on activation of oncogenic Kirsten rat sarcoma viral oncogene homolog (Kras) and loss of p53 function. Therapeutic delivery of miR-34a, a p53-regulated tumor suppressor miRNA, restored miR-34a levels in lung tumors, specifically down-regulated miR-34a target genes, and slowed tumor growth. The delivery of siRNAs targeting Kras reduced Kras gene expression and MAPK signaling, increased apoptosis, and inhibited tumor growth. The combination of miR-34a and siRNA targeting Kras improved therapeutic responses over those observed with either small RNA alone, leading to tumor regression. Furthermore, nanoparticle-mediated small RNA delivery plus conventional, cisplatin-based chemotherapy prolonged survival in this model compared with chemotherapy alone. These findings demonstrate that RNA combination therapy is possible in an autochthonous model of lung cancer and provide preclinical support for the use of small RNA therapies in patients who have cancer., National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant P30-CA14051), National Institutes of Health (U.S.) (Grant 2-PO1-CA42063), National Institutes of Health (U.S.) (Grant RO1-EB000244), National Institutes of Health (U.S.) (Grant RO1-CA115527), National Institutes of Health (U.S.) (Grant RO1-CA132091), National Cancer Institute (U.S.) (1K99CA169512), American Association for Cancer Research (Fellowship), Leukemia & Lymphoma Society of America (Fellowship), National Science Foundation (U.S.). Graduate Research Fellowship Program, Massachusetts Institute of Technology. Presidential Fellowship, United States. Dept. of Defense (National Defense Science and Engineering Graduate Fellowship)