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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,7,19]]},"abstract":"<jats:p>\n                    The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making\n                    <jats:italic>\n                      KRAS\n                      <jats:sup>MUT<\/jats:sup>\n                    <\/jats:italic>\n                    cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)\u2013conjugated antisense oligonucleotides (ASOs) for potent in\u00a0vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects associated with DNA\u2013protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non\u2013small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush\u2013ASO conjugate is a promising therapeutic platform for the treatment of\n                    <jats:italic>KRAS<\/jats:italic>\n                    -driven human cancers and warrant further preclinical and clinical development.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2113180119","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T14:34:36Z","timestamp":1657809276000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":42,"title":["Targeting oncogenic KRAS with molecular brush-conjugated antisense oligonucleotides"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0923-0027","authenticated-orcid":false,"given":"Dali","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3897-2529","authenticated-orcid":false,"given":"Qiwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiru","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1069-7265","authenticated-orcid":false,"given":"Xueguang","family":"Lu","sequence":"additional","affiliation":[{"name":"David H. 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Chemical Biology, Northeastern University, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqi","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8182-6522","authenticated-orcid":false,"given":"Sijia S.","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4561-5688","authenticated-orcid":false,"given":"Jean 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