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Herein, we report that the inclusion of aminopolycarboxylic acid conjugated lipids, such as EDTA\u2010 or DTPA\u2010hexadecylamide lipids in liposome\u2010like porphyrin nanoparticles (PS) enhanced their intracellular uptake by 25\u2010fold, which was attributed to these lipids\u2019 ability to fluidize the cell membrane in a detergent\u2010like manner rather than by metal chelation of EDTA or DTPA. EDTA\u2010lipid\u2010incorporated\u2010PS (ePS) take advantage of its unique active uptake mechanism to achieve &gt;95\u2009% photodynamic therapy (PDT) cell killing compared to &lt;5\u2009% cell killing by PS. In multiple tumor models, ePS demonstrated fast fluorescence\u2010enabled tumor delineation within minutes post\u2010injection and increased PDT potency (100\u2009% survival rate) compared to PS (60\u2009%). This study offers a new nanoparticle cellular uptake strategy to overcome challenges associated with conventional drug delivery.<\/jats:p>","DOI":"10.1002\/anie.202218218","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T03:20:06Z","timestamp":1677036006000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Novel Strategy to Drive the Intracellular Uptake of Lipid Nanoparticles for Photodynamic Therapy"],"prefix":"10.1002","volume":"62","author":[{"given":"Tiffany","family":"Ho","sequence":"first","affiliation":[{"name":"Princess Margaret Cancer Centre University Health Network  101 College Street, PMCRT 5-354 Toronto ON M5G1L7 Canada"},{"name":"Department of Pharmaceutical Sciences University of Toronto  144 College St. Toronto Toronto ON M5S 3M2 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keegan","family":"Guidolin","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre University Health Network  101 College Street, PMCRT 5-354 Toronto ON M5G1L7 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Makky","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay CNRS Institut Galien Paris-Saclay, B\u00e2timent Henri Moissan  91400 Orsay France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Valic","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre University Health Network  101 College Street, PMCRT 5-354 Toronto ON M5G1L7 Canada"},{"name":"Institute of Biomedical Engineering University of Toronto  64 College St. Toronto ON M5S 3G9 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Ding","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre University Health Network  101 College Street, PMCRT 5-354 Toronto ON M5G1L7 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiachuan","family":"Bu","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre University Health Network  101 College Street, PMCRT 5-354 Toronto ON M5G1L7 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Zheng","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre University Health Network  101 College Street, PMCRT 5-354 Toronto ON M5G1L7 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miffy H. 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