Therapeutic 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 addressing these issues and developing well-tolerated, highly-loaded carriers that are dispersible within local neural parenchyma. Here, we synthesized biodegradable trehalose-based polyelectrolyte oligomers using facile A2:B3:AR thiol-ene Michael addition reactions that form complex coacervates upon mixing of oppositely charged oligomers. Coacervates permit high concentration loading and controlled release of bioactive growth factors, enzymes, and antibodies, with modular formulation parameters that confer tunable release kinetics. Coacervates are cytocompatible with cultured neural cells and can be formulated to either direct intracellular protein delivery or sequester media containing proteins and remain extracellular. Coacervates serve as effective vehicles for precisely 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.

中文翻译：

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基于海藻糖的凝聚层，用于将局部生物活性蛋白递送至中枢神经系统


使用散装生物材料将局部生物分子输送到中枢神经系统（CNS）的治疗效果受到药物负载不足、神经纤维破坏和严重异物反应的限制。有效的中枢神经系统递送需要解决这些问题并开发可分散在局部神经实质内的耐受性良好、高负载的载体。在这里，我们使用简单的 A2:B3:AR 硫醇-烯迈克尔加成反应合成了可生物降解的海藻糖基聚电解质低聚物，该反应在混合带相反电荷的低聚物时形成复杂的凝聚层。凝聚层允许生物活性生长因子、酶和抗体的高浓度负载和受控释放，并具有可调节释放动力学的模块化配方参数。凝聚层与培养的神经细胞具有细胞相容性，并且可以配制为直接细胞内蛋白质递送或隔离含有蛋白质的培养基并保持在细胞外。凝聚层是在实质内注射后将生物分子（包括生物活性神经营养素）精确递送至小鼠纹状体的有效载体。这些结果支持使用基于海藻糖的凝聚层作为中枢神经系统疾病的治疗性蛋白质递送策略的一部分。