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Drug delivery to TBI remains a challenge due to the blood\u2010brain barrier and increased intracranial pressure. In this work, a chemical targeting approach to improve delivery of materials to the injured brain, is developed. It is hypothesized that the provisional fibrin matrix can be harnessed as an injury\u2010specific scaffold that can be targeted by materials via click chemistry. To accomplish this, the brain clot is engineered in situ by delivering fibrinogen modified with strained cyclooctyne (SCO) moieties, which incorporated into the injury lesion and is retained there for days. Improved intra\u2010injury capture and retention of diverse, clickable azide\u2010materials including a small molecule azide\u2010dye, 40\u00a0kDa azide\u2010PEG nanomaterial, and a therapeutic azide\u2010protein in multiple dosing regimens is subsequently observed. To demonstrate therapeutic translation of this approach, a reduction in reactive oxygen species levels in the injured brain after delivery of the antioxidant catalase, is achieved. Further, colocalization between azide and SCO\u2010fibrinogen is specific to the brain over off\u2010target organs. Taken together, a chemical targeting strategy leveraging endogenous clot formation is established which can be applied to improve therapeutic delivery after TBI.<\/jats:p>","DOI":"10.1002\/adma.202301738","type":"journal-article","created":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T06:44:51Z","timestamp":1716446691000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Reprograming Clots for In Vivo Chemical Targeting in Traumatic Brain Injury"],"prefix":"10.1002","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6010-8839","authenticated-orcid":false,"given":"Rebecca M.","family":"Kandell","sequence":"first","affiliation":[{"name":"Shu Chien\u2010Gene Lay Department of Bioengineering University of California  San Diego La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4422-4850","authenticated-orcid":false,"given":"Jason 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