Reprogramming Clots for in Vivo Chemical Targeting in Traumatic Brain Injury

Abstract Traumatic brain injury (TBI) is a critical public health concern, yet there are no therapeutics available to improve long‐term outcomes. Drug delivery to TBI remains a challenge due to the blood‐brain 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‐specific 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‐injury capture and retention of diverse, clickable azide‐materials including a small molecule azide‐dye, 40 kDa azide‐PEG nanomaterial, and a therapeutic azide‐protein 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‐fibrinogen is specific to the brain over off‐target organs. Taken together, a chemical targeting strategy leveraging endogenous clot formation is established which can be applied to improve therapeutic delivery after TBI.