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Robust cytosolic protein delivery requires both efficient protein binding with delivery vehicles and effective protein release after cell internalization. Although a variety of stimuli-responsive carriers have been designed, simultaneously integrating these two functions in one versatile carrier is challenging. Herein, we developed a polyamidoamine (PAMAM)-based polymer with an intracellular pHactuated hydrophobic-to-hydrophilic transition for this purpose. The polymer (designated as G5-C4) was synthesized by appending N,Ndibutylaminoethyl moieties to the peripheral amino groups of PAMAM dendrimer generation 5. Assisted by hydrophobic interactions, G5-C4 formed condensed nanoparticles with proteins and remained stable under physiological conditions. After efficient cell internalization, G5-C4 underwent a hydrophobic-to-hydrophilic transition at acidic endosomal pH, and thus promoted protein release and endosomal escape, which was verified by structure-activity relationship studies. Furthermore, both in vitro and in vivo studies indicated that G5-C4 achieved superior antitumor effect. This study provides a simple but effective design for stimuliresponsive cytosolic protein delivery.

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