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This review critically examines the dual functional nature of endothelial TLR4, delineating how it transitions into a primary driver of vascular aging and organ\u2010specific vascular pathologies. The profound spatial, temporal, and cellular heterogeneities of TLR4 signaling expose the fundamental inadequacies of conventional systemic pan\u2010TLR4 blockade, which has repeatedly failed in clinical trials due to severe immunosuppression and metabolic disruptions. To bypass these limitations, we propose a precision senotherapeutic framework utilizing advanced drug delivery systems\u2014such as Vascular cell adhesion molecule\u20101 (VCAM\u20101) or E\u2010selectin\u2010targeted nanoparticles and genetically engineered plant\u2010derived exosomes\u2014to compartmentalize TLR4 inhibition within pathologically altered endothelial sub\u2010populations. By shifting the clinical paradigm from indiscriminate receptor suppression to spatiotemporal fine\u2010tuning, this conceptual framework provides a rational blueprint for next\u2010generation anti\u2010aging therapies aimed at restoring vascular homeostasis throughout the aging process.<\/jats:p>","DOI":"10.1111\/acel.70757","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:18:10Z","timestamp":1791274690000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Endothelial\n                    <scp>TLR4<\/scp>\n                    at the Crossroads of Vascular Senescence and Targeted Senotherapeutics"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6780-1133","authenticated-orcid":false,"given":"Hyo\u2010Jin","family":"Kim","sequence":"first","affiliation":[{"name":"Division of Life Science, College of Natural Sciences Gyeongsang National 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