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

SUMMARY Proteins drugs own the large shares 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 barriers for cancer theragnostics. The phenylboronic acid modified polycations (PCD) were synthesised to assembly with enzymes and shield its activity in the blood circulation. When reached tumor site, the PCD nanoclusters effectively transported the enzymes into the cells, followed by recovering its catalysis activity after charged with ATP. Importantly, the cascaded enzyme systems (GOx&HRPA) selectively induced starvation therapy as well as PA 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 towards intracellular target.