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Regulated by microenvironments in specific applications, macrophages have a heterogenous nature and exist in different phenotypes with diverse functions, e.g., pro\u2010inflammatory and anti\u2010inflammatory. However, it is not clear whether macrophage phenotype affects nucleic acid delivery, and which one is harder to transfect, and the design of nucleic acid carriers in harder\u2010to\u2010transfect macrophage phenotypes is largely unexplored. Herein, it is first revealed that nucleic acid delivery efficacy in macrophages is influenced by phenotype: IL\u20104\u2010treated \u201cM2\u2010like\u201d macrophages with suppressed mammalian target of rapamycin complex 1 (mTORC1) levels are harder\u2010to\u2010transfect than \u201cM1\u2010like\u201d macrophages for mRNA and DNA. This knowledge is then translated to the purpose\u2010design of gene delivery carriers for harder\u2010to\u2010transfect M2 phenotype macrophages dominant upon bacteria immune evasion. By loading chloroquine in tetrasulfide bond\u2010containing organosilica nanoparticles, the resultant composite promotes macrophage M2 polarization to M1 and increases mTORC1 levels for enhanced translation. The design is demonstrated in vitro and in vivo for pathogenic\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    (\n                    <jats:italic>E. coli<\/jats:italic>\n                    ) and methicillin\u2010resistant\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    (MRSA) infections. It is expected that the findings may provide new knowledge and gene delivery solutions in other applications where the M2 phenotype macrophage is dominant.\n                  <\/jats:p>","DOI":"10.1002\/adma.202401504","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T03:19:59Z","timestamp":1731986399000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Rational Design of Advanced Gene Delivery Carriers: Macrophage Phenotype Matters"],"prefix":"10.1002","volume":"37","author":[{"given":"Yue","family":"Wang","sequence":"first","affiliation":[{"name":"Australian Institute for Bioengineering and Nanotechnology The University of Queensland  Brisbane Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yining","family":"Yao","sequence":"additional","affiliation":[{"name":"School of Chemistry and Molecular Engineering East China Normal University  Shanghai 200241 P. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Australian Institute for Bioengineering and Nanotechnology The University of Queensland  Brisbane Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Yu","sequence":"additional","affiliation":[{"name":"Australian Institute for Bioengineering and Nanotechnology The University of Queensland  Brisbane Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangqi","family":"Luo","sequence":"additional","affiliation":[{"name":"Australian Institute for Bioengineering and Nanotechnology The University of Queensland  Brisbane Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Sweet","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience (IMB) and Australian Infectious Diseases Research Centre The University of Queensland  Brisbane Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3707-0785","authenticated-orcid":false,"given":"Chengzhong","family":"Yu","sequence":"additional","affiliation":[{"name":"Australian Institute for Bioengineering and Nanotechnology The University of Queensland  Brisbane Queensland 4072 Australia"},{"name":"School of Chemistry and Molecular Engineering East China Normal University  Shanghai 200241 P. 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