Hollow broad-spectrum nanozymes can degrade intracellular RNA in the presence of ribonuclease inhibitors (RIs) in a non-sequence-specific fashion. RNA translates genetic information into proteins constituting cell structures and crucial molecular regulators, playing essential roles in living organisms. Additionally, it regulates gene expression during development, cellular differentiation, and changing environments. Given the important role of RNA in gene and cell regulation, RNA intervention and targeting provide a prime opportunity to develop therapeutic agents for treating genetic diseases such as cancer. Currently, there are two major therapeutic strategies to target RNA: nucleic acid-based and ribonuclease (RNase)-based. RNase-based therapies leverage the ability of ribonucleases to degrade a broad spectrum of RNA molecules and constitute important alternatives to traditional highly toxic DNA damaging and intracellular exogenous RNA degradation compounds in fighting cancer and pathogen infections. However, inactivation of RNase activity by ribonuclease inhibitors (RIs) is an important obstacle that these therapies face, leading to high dose requirements to overcome inactivation, as well as poor therapeutic efficiency. For this reason, evading cellular RIs becomes crucial for RNase drugs to be effective in targeting cancer or pathogenic infections.
Researchers at the University of Florida have designed broad-spectrum nanozymes composing ribonucleases, featuring the ability to degrade intracellular RNAs in the presence of RNAse inhibitors in a non-sequence-specific manner. These nanozymes show high enzymatic activity in RNA degradation as well as high cellular uptake rates.
Broad-spectrum nanozymes for active and non-specific intracellular RNA degradation in the presence of RNase inhibitors
These broad-spectrum nanozymes actively degrade intracellular RNA in a non-sequence-specific manner and in the presence of cytosolic RNase inhibitors (RIs). The nanozymes display enhanced cellular uptake rates and enzymatic activities in RNA degradation and can effectively manipulate the functions of living cells by degrading a broad spectrum of intracellular RNA, ensuring strong anticancer effects and antiviral efficacy against RNA viruses. Additionally, they contain traffic-guiding moieties, providing selective cellular entry properties and elevating their target specificity. This nanozyme design comprises the co-assembly of single-stranded capturer DNA and ribonucleases onto a nanoscopic surface using gold nanoparticles as scaffolds. The DNA molecules with a specifically designed sequence bind to target RNAs through Watson-Crick base pairing, then directing the neighboring ribonucleases to cleave the captured RNA molecules. By reducing the length or surface loading density of these single-stranded DNA oligonucleotides, the nanozymes can significantly decrease their RNA sequence specificity, while still retaining their ability to evade RIs. An aqueous KCN solution removes the gold scaffolds to avoid potential toxicity during long-term treatments.