Circular Single‐Stranded DNA‐Based Artificial Nanoviruses Mitigate Colorectal Cancer Development

Abstract Colorectal cancer (CRC) remains a significant global health challenge, underscoring the need for innovative therapeutic strategies. Oncogenic miRNAs (oncomiRs) play a significant biological role in the initiation and progression of colorectal cancer. Inspired by the cooperative mechanisms of plant nanovirus, which employ multiple circular single‐stranded DNA (CssDNA) genomes, it is hypothesized that the development and delivery of CssDNA to target oncomiRs would achieve therapeutic benefits in CRC. In this study, a multi‐omics approach is utilized to identify key tumor suppressor genes (TSGs) and their related oncomiRs implicated in CRC, followed by the development of CssDNA, each of which is loaded with multiple miRNA binding sites targeting one oncomiR. When transfected into the cells, these CssDNA can effectively target and sequester the corresponding oncomiRs to restore the expression of TSGs, leading to a marked reduction in CRC development both in vitro and in vivo. The findings highlight the therapeutic potential of nanovirus‐inspired CssDNA in modulating the miRNA‐mediated regulatory network in CRC. This study lays the groundwork for the development of non‐coding DNA‐based therapies with broad implications for the treatment of colorectal cancer and potentially other malignancies.