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Gene therapy works by employing cationic polymers, liposomes, and nanoparticles to condense DNA into polyplexes via electronic interactions. Then, a therapeutic gene is introduced into target cells, thereby restoring or changing cellular function. However, gene transfection efficiency remains low in vivo due to high protein binding, poor targeting ability, and substantial endosomal entrapment. Artificial sheaths containing PEG, anions, or zwitterions can be introduced onto the surface of gene carriers to prevent interaction with proteins; however, they reduce the cellular uptake efficacy, endosomal escape, targeting ability, thereby, lowering gene transfection. Here, it is reported that linking dipicolylamine\u2010zinc (DPA\u2010Zn) ions onto polyplex nanoparticles can produce a strong hydration water layer around the polyplex, mimicking the function of PEGylation to reduce protein binding while targeting cancer cells, augmenting cellular uptake and endosomal escape. 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This strategy provides a new solution for preventing protein adsorption while improving cellular uptake and endosomal escape.<\/jats:p>","DOI":"10.1002\/adhm.202203252","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T05:39:58Z","timestamp":1683524398000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["DPA\u2010Zinc around Polyplexes Acts Like PEG to Reduce Protein Binding While Targeting Cancer Cells"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7757-9538","authenticated-orcid":false,"given":"Xuan","family":"Nie","sequence":"first","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China  Hefei Anhui 230026 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