Sequence-specific and programmable catalytic degradation of extracellular microRNAs by membrane-anchored DNA nanomachines

Extracellular microRNAs (miRNAs) contribute to metastasis through communication between tumour cells and their microenvironment, yet their sustained, sequence-selective depletion remains challenging. Here we report Programmable RNA-Intercepting Molecular Eraser (PRIME), a membrane-anchored DNA nanomachine that organizes miRNA recognition and catalytic degradation at the cell surface. A double-tetrahedral DNA scaffold positions a programmable recognition hairpin beside RNase H. Target binding generates an RNA/DNA hybrid for RNase H-mediated cleavage, and product release resets the hairpin for subsequent degradation cycles. Membrane-anchored PRIME depleted matched extracellular miRNAs by 70.6-89.4% across lung, breast and cervical cancer cell models. Multi-target PRIME (M-PRIME) inhibited migration by 71.3-96.0% in Transwell assays across these models. To evaluate its therapeutic potential, we established an orthotopic lung-tumour model and an early-intervention breast-cancer lung-colonization model in mice. Aptamer-directed M-PRIME combined with gemcitabine reduced pulmonary tumour burden by 74.5% in established lung tumours and 93.2% in the lung-colonization model. These effects were consistent with PRIME-mediated extracellular miRNA degradation, with circulating target miRNA levels reduced by 77.5-98.7% relative to gemcitabine alone. Together, these findings establish a programmable material strategy for sustained extracellular RNA depletion and support its potential to enhance chemotherapy in preclinical tumour models.