Modular Assembly of Tumor‐Penetrating and Oligomeric Nanozyme Based on Intrinsically Self‐Assembling Protein Nanocages

Biomimetic design of nanomaterials with enzyme‐like characteristics has emerged as a promising method for the generation of novel therapeutics. However, synthesis of nanomaterials while maintaining a high degree of control over both geometry and valency poses a prominent challenge. Herein, the authors introduce a nanomaterial‐based synthetic biology strategy for accurate and quantitative tailoring of high‐ordered nanostructures that uses a “bottom‐up” hierarchical incorporation of protein building blocks. The assembled nano‐oligomers possessed tunable protein motifs and multivalent binding domains, which facilitated prolonged blood circulation time, accumulation within tumor cells through direct targeting of cell receptors, and deep tumor tissue penetration via a transcytosis mechanism. Using these protein/protein nano‐oligomers as scaffolds, the authors created a new series of artificial nano‐scaled metalloenzymes (nanozymes) by the in situ incorporation of metal nanoclusters within the cavity of the protein nanocages. Nanozymes were capable of mimicking peroxidase‐like activity and generated cytotoxic free radicals. Compared to nanozyme alone, the systemic delivery of oligomeric nanozymes demonstrated significantly enhanced therapeutic and anti‐tumor benefits. This study shows a new insight into nanotechnology by taking advantage of synthetic biotechnology. It remains challenging to precisely control and reproducibly formulate nanomedicines. A nanomaterial‐based synthetic biology strategy is established for tailoring oligomeric nanostructures and a series of artificial metalloenzymes in a precisely controlled manner, which offers an option for tailored anticancer nanomedicines that have a high degree of control over both geometry and valency.