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However, even in diseased organs, both normal and stressed, dying cells coexist, and a targeted delivery system specifically for dying cells has yet to be explored to mitigate off-target effects within the same organ. This study aimed to establish such a system. By examining the surfaces of dying cells in vitro, we identified P-selectin glycoprotein ligand-1 (PSGL-1) as a universal marker for dying cells, positioning it as a potential target for selective drug delivery. We demonstrated that liposomes conjugated with the PSGL-1 binding protein P-selectin had significantly greater binding efficiency to dying cells compared to control proteins such as E-selectin, L-selectin, galectin-1, and C-type lectin-like receptor 2. Using thioacetamide (TAA) to induce hepatitis and hepatocyte damage in mice, we assessed the effectiveness of our P-selectin-based delivery system. In vivo, P-selectin-conjugated liposomes effectively delivered fluorescent dye and the apoptosis inhibitor z-DEVD to TAA-damaged livers in wild-type mice, but not in PSGL-1 knockout mice. In TAA-treated wild-type mice, unconjugated liposomes required a 100-fold higher z-DEVD dose compared to P-selectin-conjugated liposomes to achieve a comparable, albeit less effective, therapeutic outcome in lowering plasma alanine transaminase levels and alleviating thrombocytopenia. This emphasizes that P-selectin conjugation enhances drug delivery efficiency by approximately 100-fold in mice. These results suggest that P-selectin-based liposomes could be a promising strategy for targeted drug delivery, enabling both diagnosis and treatment by specifically delivering cell-labeling agents and rescue agents to dying cells via the P-selectin\u2013PSGL-1 axis at the individual cell level.<\/jats:p>","DOI":"10.3390\/cells13211778","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T05:07:22Z","timestamp":1730092042000},"page":"1778","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeted Delivery to Dying Cells Through P-Selectin\u2013PSGL-1 Axis: A Promising Strategy for Enhanced Drug Efficacy in Liver Injury Models"],"prefix":"10.3390","volume":"13","author":[{"given":"Te-Sheng","family":"Lien","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1994-7355","authenticated-orcid":false,"given":"Der-Shan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8731-3485","authenticated-orcid":false,"given":"Hsin-Hou","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Nkune, N.W., and Abrahamse, H. 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