{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T04:02:07Z","timestamp":1784692927339,"version":"3.55.0"},"reference-count":31,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Smart Molecules"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>A fundamental constraint of conventional messenger RNA (mRNA) delivery systems is their obligatory trafficking through endosomal\u2013lysosomal compartments, wherein cargo degradation and activation of endosomal Toll\u2010like receptors precipitate substantial translational attrition and deleterious inflammatory cascades. We herein report a chemically engineered platform that circumvents these limitations ab initio. Through strategic perfluoro\u2010acylation of branched polyethyleneimine (PEI, 25\u00a0kDa) with pentafluoropropionic anhydride, we install approximately 26 fluoro\u2010amide \u201czipper\u201d moieties per polymer chain that orchestrate direct, energy\u2010independent trans\u2010bilayer translocation without recruitment of clathrin, caveolae, or lipid raft microdomains\u2014thereby precluding lysosomal entrapment and catabolism. Bio\u2010orthogonal copper\u2010free click chemistry between azide\u2010 and dibenzocyclooctyne (DBCO)\u2010terminated PEI\u2010F derivatives, coupled with redox\u2010labile disulfide crosslinkers, engenders polyplexes of exceptional extracellular stability that undergo quantitative glutathione\u2010triggered disassembly within the cytosolic milieu. This endosome\u2010evasive entry mechanism effectively sequesters single\u2010stranded mRNA from Toll\u2010like receptor 3, TLR7, and TLR8 surveillance, establishing a \u201cTLR\u2010attenuated\u201d delivery paradigm characterized by undetectable interferon\u2010\u03b1, interferon\u2010\u03b2, TNF\u2010\u03b1, and IL\u20106 induction. In human umbilical vein endothelial cells, GFP\u2010mRNA transfection exceeds 90% fluorescent positivity with 4.8\u2010fold superior luciferase expression relative to Lipofectamine\u2122 3000, whilst maintaining &gt;95% viability. Therapeutic translatability is demonstrated in a murine hindlimb ischemia model, wherein a single 10\u00a0\u03bcg intramuscular dose of mVEGF\u2010A polyplexes restores blood perfusion to 118% of baseline within 28 days\u2014representing marked superiority over the commercial gold standard and effectuating complete tissue salvage without necrosis. Comprehensive hematological and immunological profiling corroborates the absence of hematotoxicity, systemic inflammation, or innate immune activation. This modular, purely synthetic platform resolves the classical stability\u2013availability paradox whilst eliminating the immunogenic liabilities inherent to endocytic delivery, furnishing a readily translatable scaffold for precision regenerative medicine.<\/jats:p>","DOI":"10.1002\/smo2.70085","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T03:13:38Z","timestamp":1784690018000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Endocytosis\u2010independent cytosolic entry of messenger RNA via fluorous bilayer zippering attenuating Toll\u2010like receptor signaling and enables ischemic tissue salvage"],"prefix":"10.1002","author":[{"given":"Yue","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gastric Surgery Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital &amp; Institute)  Shenyang China"},{"name":"Provincial Key Laboratory of Interdisciplinary Medical Engineering for Gastrointestinal Carcinoma Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital &amp; Institute)  Shenyang China"},{"name":"Immunotherapy &amp; Tumor Metabolism\u2010Microecology Research Unit Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital &amp; Institute)  Shenyang China"},{"name":"Department of Gastric Surgery Cancer Hospital of China Medical University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of International Medical Services Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital &amp; Institute)  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqing","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Endoscopy Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital &amp; Institute)  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhua","family":"Li","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6184-0658","authenticated-orcid":false,"given":"Changgui","family":"Tong","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9386-9287","authenticated-orcid":false,"given":"Hongyan","family":"Cui","sequence":"additional","affiliation":[{"name":"Innovation Center of Yangtze River Delta Zhejiang University  Jiaxing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qixian","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastric Surgery Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital &amp; Institute)  Shenyang China"},{"name":"Provincial Key Laboratory of Interdisciplinary Medical Engineering for Gastrointestinal Carcinoma Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital &amp; Institute)  Shenyang China"},{"name":"Innovation Center of Yangtze River Delta Zhejiang University  Jiaxing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2721-0337","authenticated-orcid":false,"given":"Haidong","family":"Li","sequence":"additional","affiliation":[{"name":"Provincial Key Laboratory of Interdisciplinary Medical Engineering for Gastrointestinal Carcinoma Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital &amp; Institute)  Shenyang China"},{"name":"MOE Key Laboratory of Bio\u2010Intelligent Manufacturing School of Bioengineering Dalian University of Technology  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7760-916X","authenticated-orcid":false,"given":"Yan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Gastric Surgery Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital &amp; Institute)  Shenyang China"},{"name":"Provincial Key Laboratory of Interdisciplinary Medical Engineering for Gastrointestinal Carcinoma Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital &amp; Institute)  Shenyang China"},{"name":"Department of Gastric Surgery Cancer Hospital of China Medical University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/s41568-023-00586-2","volume":"23","author":"Liu C.","year":"2023","journal-title":"Nat. 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