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

Abstract

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.

Recent Advances in Nanozymes: From Matters to Bioapplications

“…First of all, more exploration should be carried out for the matters that are used to fabricate nanozymes. [ 233 ] Materials, such as up‐conversion nanomaterials, sub‐nanometer materials and high‐entropy alloy can be used for the preparation of nanozymes. What's more, single‐atom catalysts have become a new frontier in nanozymology due to their maximum metallic atom utilization, high activity, and selectivity.…”

Nanozymes for Regenerative Medicine

“…Catalytic therapy for cancer [90] Liposomes High biocompatibility, nanozymes co-delivery, enhanced accumulation in a targeted site…”

“…The liposome nanoplatform not only effectively combined chemodynamic therapy, photothermal therapy, and drug therapy, but also significantly limited antibiotic dosage and bacterial resistance, further contributing to the in vivo safety of nanozymes and antibiotics. [90] Additionally, based on numerous investigations, it is reasonable to consider liposomes as an outstanding platform for the construction of versatile nanozymes. For illustration, Feng et al prepared PEG modified liposomes loading ultrasmall Ir nanozymes with CAT-like activity, alleviating hypoxia by decomposition endogenous H 2 O 2 into oxygen under near infrared (NIR) light irradiation.…”

Manipulating Cell Fates with Protein Conjugates

“…Radionuclides can also be loaded into protein-oligonucleotide conjugates for radiotherapy . Protein–polymer conjugates have also been generated and self-assembled into nanoparticles for the encapsulation and delivery of cancer drugs , (Figure C). For example, bovine serum albumin (BSA) is a commonly used protein scaffold for conjugation with hydrophobic polymers, and the resulting BSA-polymer nanoparticles have been used to deliver drugs, such as doxorubicin and camptothecin .…”

“…Moreover, other proteins without targeting capabilities have also been developed to serve as functional building blocks for protein conjugate construction. For several of these proteins, their self-assembling properties or favorable biocompatibility has been used to facilitate the fabrication of new supramolecular structures, as well as reversible function when encountering specific stimuli. − All these proteins possess unique functionalities that can be used to prepare new assemblies whose properties can be tailored to fulfill distinct objectives related to the programing of cellular activities.…”