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However, current T cell engineering approaches rely heavily on ex vivo manipulation, which is labor\u2010intensive, costly, and can alter cell phenotypes. Lipid nanoparticles (LNPs) offer a scalable nonviral alternative, yet conventional formulations show minimal interaction with lymphocytes and are rapidly cleared by the liver. In this study, we develop a modular DBCO\u2010azide click\u2010chemistry approach to functionalize LNPs with a high\u2010affinity CD4 nanobody, enabling precise CD4 receptor\u2010directed delivery to human CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Optimized CD4\u2010targeted LNPs transfect up to 48% of non\u2010activated CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells within a PBMC co\u2010culture, the highest efficiency reported so far through LNP transfection. Moreover, they successfully deliver CRISPR\u2010Cas9 components to activated CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and achieve up to 32% gene editing. In humanized NSG\u2010SGM3 mice, CD4\u2010targeted LNPs selectively associate with and transfect circulating and bone marrow\u2013resident human CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells while showing minimal off\u2010target activity in murine cells. These results establish CD4\u2010nanobody LNPs as a versatile platform for targeted mRNA and gene\u2010editing delivery, with broad potential for cancer immunotherapy, T cell reprogramming, and HIV cure strategies.\n                  <\/jats:p>","DOI":"10.1002\/adhm.71747","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T03:14:05Z","timestamp":1789960445000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Click\u2010Chemistry Functionalized Lipid Nanoparticles for In Vitro and In Vivo Transfection of Primary Human CD4\n                    <sup>+<\/sup>\n                    T Cells"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6157-3684","authenticated-orcid":false,"given":"Maaike","family":"De Cock","sequence":"first","affiliation":[{"name":"HIV Cure Research Center, Department of Internal Medicine and Pediatrics Faculty of Medicine and Health Sciences Ghent University  Belgium"},{"name":"Biopharmaceutical Technology Unit, Department of Pharmaceutics, Faculty of Pharmaceutics Ghent University  Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elianne","family":"Burg","sequence":"additional","affiliation":[{"name":"HIV Cure Research Center, Department of Internal Medicine and Pediatrics Faculty of Medicine and Health Sciences Ghent University  Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Gerlo","sequence":"additional","affiliation":[{"name":"HIV Cure Research Center, Department of Internal Medicine and Pediatrics Faculty of Medicine and Health Sciences Ghent University  Belgium"},{"name":"Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences Ghent University  Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linos","family":"Vandekerckhove","sequence":"additional","affiliation":[{"name":"HIV Cure Research Center, Department of Internal Medicine and Pediatrics Faculty of Medicine and Health Sciences Ghent University  Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno G.","family":"De Geest","sequence":"additional","affiliation":[{"name":"Biopharmaceutical Technology Unit, Department of Pharmaceutics, Faculty of Pharmaceutics Ghent University  Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolien","family":"Van Cleemput","sequence":"additional","affiliation":[{"name":"HIV Cure Research Center, Department of Internal Medicine and Pediatrics Faculty of Medicine and Health Sciences Ghent University  Belgium"},{"name":"Laboratory of Virology, Department of Translational Physiology, Infectiology, and Public Health, Faculty of Veterinary Medicine Ghent University  Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102008"},{"key":"e_1_2_11_3_1","unstructured":"M. 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