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Several block copolymers are developed by varying nonionic hydrophilic blocks (poly(2\u2010methyl\u20102\u2010oxazoline) (pMeOx) or poly(2\u2010ethyl\u20102\u2010oxazoline) (pEtOx), cationic blocks, and an optional hydrophobic block (poly(2\u2010isopropyl\u20102\u2010oxazoline) (iPrOx). The cationic blocks are produced by side chain modification of 2\u2010methoxy\u2010carboxyethyl\u20102\u2010oxazoline (MestOx) block precursor with diethylenetriamine (DET) or tris(2\u2010aminoethyl)amine (TREN). For the attachment of a targeting ligand, mannose, azide\u2010alkyne cycloaddition click chemistry methods are employed. Of the two cationic side chains, polyplexes made with DET\u2010containing copolymers transfect macrophages significantly better than those made with TREN\u2010based copolymer. Likewise, nontargeted pEtOx\u2010based diblock copolymer is more active in cell transfection than pMeOx\u2010based copolymer. The triblock copolymer with hydrophobic block iPrOx performs poorly compared to the diblock copolymer which lacks this additional block. Surprisingly, attachment of a mannose ligand to either copolymer is inhibitory for transfection. Despite similarities in size and design, mannosylated polyplexes result in lower cell internalization compared to nonmannosylated polyplexes. Thus, PEG\u2010free, nontargeted DET\u2010, and pEtOx\u2010based diblock copolymer outperforms other studied structures in the transfection of macrophages and displays transfection levels comparable to GeneJuice, a commercial nonlipid transfection reagent.<\/jats:p>","DOI":"10.1002\/mabi.202300177","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T07:49:02Z","timestamp":1689752942000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Poly(2\u2010oxazoline)\u2010Based Polyplexes as a PEG\u2010Free Plasmid DNA Delivery Platform"],"prefix":"10.1002","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8813-4000","authenticated-orcid":false,"given":"Dina N.","family":"Yamaleyeva","sequence":"first","affiliation":[{"name":"Joint UNC\u2010CH and NC State Department of Biomedical Engineering University of North Carolina at Chapel Hill  Chapel Hill NC 27599\u20107575 USA"},{"name":"Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill  Chapel Hill NC 27599\u20107575 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Makita","sequence":"additional","affiliation":[{"name":"Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill  Chapel Hill NC 27599\u20107575 USA"},{"name":"Formulation Research &amp; Development Laboratories, Technology Research &amp; Development Sumitomo Pharma Co., Ltd.  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