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Especially nonviral gene delivery systems are of increasing interest. However, low transgene expression levels and limited tolerability of these systems remain a challenge. The improvement of nucleic acid delivery using depolymerized chitosan\u2013polyethylenimine DNA complexes (dCS\u2010PEI\/DNA) is investigated. The secore complexes are further combined with chitosan\u2010based shells and functionalized with polyethylene glycol (PEG) and cell penetrating peptides. This modular approach allows to evaluate the effect of functional shell components on physicochemical particle characteristics and biological effects. The optimized ternary complex combines a core\u2010dCS\u2010linear PEI\/DNA complex with a shell consisting of dCS\u2010PEG\u2010COOH, which results in improved nucleic acid encapsulation, cellular uptake and transfection potency in human hepatoma HuH\u20107cells and murine primary hepatocytes. Effects on transgene expression are confirmed in wild\u2010type mice following retrograde intrabiliary infusion. After administration of only 100 ng complexed DNA, ternary complexes induced a high reporter gene signal for three days. It is concluded that ternary coreshell structured nanoparticles comprising functionalized chitosan can be used for in vitro andin vivo gene delivery.<\/jats:p>","DOI":"10.1002\/mabi.202200314","type":"journal-article","created":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T11:50:30Z","timestamp":1665057030000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Core\u2013Shell Structured Chitosan\u2010Polyethylenimine Nanoparticles for Gene Delivery: Improved Stability, Cellular Uptake, and Transfection Efficiency"],"prefix":"10.1002","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0504-0461","authenticated-orcid":false,"given":"Jens","family":"Casper","sequence":"first","affiliation":[{"name":"Division of Pharmaceutical Technology Department of Pharmaceutical Sciences University of Basel  Basel CH\u20104056 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