ATP-Charged Nanoclusters Enable Intracellular Protein Delivery and Activity Modulation for Cancer Theranostics.

Protein drugs own a large share in the market and hold great prospects for the treatment of many diseases. However, the available protein drugs are limited to the extracellular target, owing to the inefficient transduction and activity modulation of proteins targeting intracellular environment. In this study, we constructed ATP-charged platforms to overcome the above-mentioned barriers for cancer theranostics. The phenylboronic acid-modified polycations (PCD) were synthesized to assemble with enzymes and shield its activity in the blood circulation. When the PCD nanoclusters reached tumor site, they effectively transported the enzymes into the cells, followed by recovering its catalytic activity after being charged with ATP. Importantly, the cascaded enzyme systems (GOx&HRPA) selectively induced starvation therapy as well as photoacoustic imaging of tumor. Our results revealed that the intelligent nanoclusters were broadly applicable for protein transduction and enzyme activity modulation, which could accelerate the clinical translation of protein drugs toward intracellular target.