Trehalose-based coacervates for local bioactive protein delivery to the central nervous system

Abstract

SummaryTherapeutic outcomes of local biomolecule delivery to the central nervous system (CNS) using bulk biomaterials are limited by inadequate drug loading, neuropil disruption, and severe foreign body responses. Effective CNS delivery requires ad-dressing these issues and developing well-tolerated, highly-loaded carriers that are dis-persible within local neural parenchyma. Here, we synthesized biodegradable trehalose-based polyelectrolyte oligomers using facile A2:B3:AR thiol-ene Michael addition reac-tions that form complex coacervates upon mixing of oppositely charged oligomers. Co-acervates permit high concentration loading and controlled release of bioactive growth factors, enzymes, and antibodies, with modular formulation parameters that confer tuna-ble release kinetics. Coacervates are cytocompatible and readily bind to cultured neural cellsin vitrobut remain extracellularly. Coacervates serve as effective vehicles for pre-cisely delivering biomolecules, including bioactive neurotrophins, to the mouse striatum following intraparenchymal injection. These results support the use of trehalose-based coacervates as part of therapeutic protein delivery strategies for CNS disorders.