Physically Masked Nanoflares for Accurate Biological Applications by Blocking Nucleases

Abstract Nanoflare integrated with a gold nanoparticle (Au NP) core and a functional oligonucleotide shell is a powerful platform for bio‐applications, such as sensing, imaging, diagnosis, and therapy. However, degradation of nucleic acids by endogenous nucleases in vivo is an inevitable problem causing signal distortion. To solve this issue, in this work, a physically masked strategy was designed by trapping the nanoflare in a porous polymer nanocage. The porous structure of the nanocage allowed the penetration of small target molecules to react with the internal nanoflare, while bulky nucleases were blocked, resulting in high‐fidelity fluorescence signaling. Using this method, cancer cells were differentiated from normal cells by a masked nanoflare that can recognize a microRNA biomarker (miRNA‐21), and tumors were imaged with a high‐contrast signal. The physical masking strategy opened up a new path for improving the stability of nucleic acid probes against nucleases, facilitating accurate bio‐application.