Programmable Circular Single‐Stranded DNA Acts as Recyclable Anti‐miRNA Nucleotides to Inhibit Colorectal Cancer

MicroRNA (miRNA) therapy represents an attractive approach for the treatment of colorectal cancer (CRC). However, the efficacy of therapy targeting a single oncomiRNA (oncomiR) is limited, as multiple oncomiRs often act simultaneously in promoting CRC development. In addition, current anti-miRNA nucleotide (AMiN) design faces challenges, including high synthetic error rate and difficulty in synthesizing long oligonucleotides. Circular single-stranded DNA (CssDNA), an ancient form of DNA that has gained increasing attention recently, is known for its easy synthesis, high stability, low error rate, and long size potential. Here, we develop a multi-oncomiR targeting platform with low immunogenicity, high stability and long-size potential using in vivo M13 phage-generated CssDNA. This CssDNA acts as a sponge, which attracts and degrades multiple abnormally overexpressed oncomiRs in CRC. The degradation of oncomiRs promotes the expression of tumor suppressor genes (TSGs), inhibiting CRC development. Further, the degradation of oncomiRs from the sponge releases the free CssDNA for second round of action, which results in the efficacy and recyclability of CssDNA. It's visible to spread this novel, sequence customizable, multi-oncomiR targeting platform using CssDNA as a stable, low-immunogenic and recyclable AMiN in antagonizing miRNA-mediated repression of TSG expression for other tumor suppression.