Functionalization of Nanozymes: A Precision Approach to Targeted Cancer Therapy

Nanozymes are nanoscale materials that function similarly to natural enzymes, offering advantages for cancer therapy when compared with traditional biological enzymes due to their enhanced enzymatic activity, stability, versatility, low cost, and their ability to alter the tumor microenvironment. This enables new cancer treatment strategies by modulating the tumor microenvironment through chemotherapy, photothermal therapy, photodynamic therapy, or starving therapy. However, challenges persist that hinder the development and use of nanozymes for cancer treatment, including difficulties in substrate selection, ongoing issues of tumor microenvironment heterogeneity, and the risk of off-target toxicities. Therefore, developing functionalization strategies to enhance nanozyme catalytic efficiency, targeting specificity, and biocompatibility can significantly enhance the success of novel nanozymes in cancer treatment. The covalent techniques for attaching peptides, polymers, and aptamers are based on EDC/NHS coupling, Click chemistry, and Schiff-base condensation. Noncovalent attachment techniques rely on reversible interactions (e.g., hydrogen bonds, π-π stacking, and electrostatic forces) to retain the native enzyme activity. While functionalization techniques improve the tumor targeting and biodistribution of nanozymes, they also enable stimulus-responsive activation of the nanozymes in the tumor microenvironment (triggered by acidic pH, glutathione, and/or H2O2) to reduce the risk of systemic toxicity. This review comprehensively discusses the classification, catalytic principles, and therapeutic applications of nanozymes, with emphasis on their role in modulating the tumor microenvironment for effective cancer therapy. Different functionalization strategies, including covalent, noncovalent, and peptide-, ligand-, and aptamer-based approaches, will be highlighted to enhance targeting, catalytic efficiency, and clinical applicability.