The design of intracellular delivery systems for protein drugs remains a challenge due to limited delivery efficacy and serum stability. Herein, we propose a reversible assembly strategy to assemble cargo proteins and phenolic polymers into stable nanoparticles for this purpose using a heterobifunctional adaptor (2-formylbenzeneboronic acid). The adaptor is easily decorated on cargo proteins via iminoboronate chemistry and further conjugates with catechol-bearing polymers to form nanoparticles via boronate diester linkages. The nanoparticles exhibit excellent serum stability in culture media but rapidly release the cargo proteins triggered by lysosomal acidity and GSH after endocytosis. In a proof-of-concept animal model, the strategy successfully transports superoxide dismutase to retina via intravitreal injection and efficiently ameliorates the oxidative stress and cellular damage in the retina induced by ischemia-reperfusion (I/R) with minimal adverse effects. The reversible assembly strategy represents a robust and efficient method to develop serum-stable systems for the intracellular delivery of biomacromolecules.

中文翻译：

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蛋白质和酚类聚合物的可逆组装，用于具有血清稳定性的细胞内蛋白质递送

由于有限的递送功效和血清稳定性，蛋白质药物的细胞内递送系统的设计仍然是一个挑战。在此，我们提出了一种可逆组装策略，使用异双功能接头（2-甲酰基苯硼酸）将货物蛋白和酚类聚合物组装成稳定的纳米颗粒。该接头很容易通过亚氨基硼酸化学修饰在货物蛋白上，并进一步与含儿茶酚的聚合物结合，通过硼酸二酯键形成纳米颗粒。纳米粒子在培养基中表现出优异的血清稳定性，但在内吞后由溶酶体酸度和 GSH 触发快速释放货物蛋白。在概念验证动物模型中，该策略通过玻璃体内注射成功地将超氧化物歧化酶转运至视网膜，并有效改善缺血再灌注（I/R）引起的视网膜氧化应激和细胞损伤，且副作用最小。可逆组装策略代表了开发用于生物大分子细胞内递送的血清稳定系统的稳健且有效的方法。