An Enzymatically Gated Catalytic Hairpin Assembly Delivered by Lipid Nanoparticles for the Tumor‐Specific Activation of Signal Amplification in miRNA Imaging

Abstract MicroRNA (miRNA) imaging in disease sites is vital to elucidate their role in cancer progression. However, limited tumor specificity remains a major barrier for traditional amplification approaches due to associated background signal leakage. Here, we report a generalizable approach via the combination of enzymatically triggered catalytic hairpin assembly with lipid nanoparticles (LNPs)‐based delivery strategy for tumor‐specific activation of signal amplification and therefore sensitive miRNA imaging. The signal amplification is established via engineering of traditional catalytic hairpin assembly with enzymatically activated motifs to achieve triggable miRNA imaging in cancer cells. Furthermore, by the introduction of LNPs to combat biological barriers, we demonstrate that the system enables amplified miRNA imaging in vivo with reduced off‐tumor signal, leading to enhanced tumor‐to‐background contrast compared with traditional methods. This approach that relies on specific triggers and controlled delivery to distinguish miRNA in cancer cells from normal cells should be useful in tumor diagnosis.