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The most widely administered class of anticoagulants is heparin\u2010based anticoagulants such as unfractionated heparin, low\u2010molecular weight heparins (LMWHs), and fondaparinux. Protamine is the only FDA\u2010approved heparin antidote. Protamine has limited efficacy neutralizing LMWHs and no reversal activity against fondaparinux. The use of protamine can lead to complications, including excessive bleeding, hypotension, and hypersensitivity, and has narrow therapeutic window. In this work, a new concept in the design of a universal heparin antidote: switchable protonation of cationic ligands, is presented. A library of macromolecular polyanion inhibitors (MPIs) is synthesized and screened to identify molecules that can neutralize all heparins with high selectivity and reduced toxicity. MPIs are developed by assembling cationic binding groups possessing switchable protonation states onto a polymer scaffold. By strategically selecting the identity and modulating the density of cationic binding groups on the polymer scaffold, a superior universal heparin reversal agent is developed with improved heparin\u2010binding activity and increased hemocompatibility profiles leading to minimal effect on hemostasis. The activity of this heparin antidote is demonstrated using in vitro and in vivo studies.<\/jats:p>","DOI":"10.1002\/adhm.202400108","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T17:45:02Z","timestamp":1711561502000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["External Trigger Free Charge Switchable Cationic Ligands in the Design of Safe and Effective Universal Heparin Antidote"],"prefix":"10.1002","volume":"13","author":[{"given":"Chanel C.","family":"La","sequence":"first","affiliation":[{"name":"Centre for Blood Research Life Sciences Institute University of British Columbia  Vancouver BC V6T 1Z3 Canada"},{"name":"Department of Chemistry University of British Columbia  Vancouver BC V6T 1Z3 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Biological 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