Biologics play an essential role in treating various indications from cancers to the metabolic diseases, while the current development of new classes of intracellular-acting protein drugs is still hindered because of high molecular mass and overall hydrophilicity of proteins creating extremely poor permeability across cell membrane. Hence, there remains an unmet need to develop safe, potent approaches to augment intracellular protein delivery efficiency. Here, we described a facile multi-component reaction system for generating a small library of redox-responsive cationic polypeptoids with high bio-compatibility. The co-assembly of optimized polymer with protein leads to the formation of compacted nanocomplexes with smaller size and high encapsulation efficiency, thus improving cellular internalization via the macropinocytosis and/or caveolae-mediated endocytosis mainly. After endo-lysosomal escape, the nanocomplexes can be disassociated to efficiently release cargo proteins into the cytosol, owing to the intracellular glutathione (GSH)-triggered rapid cleavage of disulfide bonds in polymers backbone. As a result, we screened a promising platform reagent for efficient cytosolic protein delivery application.

生物制剂在治疗从癌症到代谢性疾病的各种适应症中起着至关重要的作用，而由于蛋白质的高分子量和整体亲水性导致跨细胞膜极差的通透性，目前仍阻碍新型细胞内作用蛋白药物的开发。因此，仍然存在开发安全，有效的方法以提高细胞内蛋白递送效率的未满足需求。在这里，我们描述了一种简便的多组分反应系统，用于生成具有高生物相容性的小型氧化还原反应性阳离子多肽库。助组件与蛋白质导致形成压实纳米复合物的具有更小尺寸和高包封率，从而提高了细胞内化优化聚合物的通过巨胞饮作用和/或小窝介导的内吞作用。溶酶体逃逸后，由于细胞内谷胱甘肽（GSH）触发了聚合物主链中二硫键的快速裂解，纳米复合物可以解离，从而有效地将货物蛋白释放到细胞质中。结果，我们筛选出了有前途的平台试剂，用于有效的胞质蛋白递送应用。