Intracellular In Situ Assembled DNA Networks Targeting Mitochondria Enable Selective Elimination of Senescent Cells and Improve Cell Viability

Abstract Mitochondria play crucial roles in energy production, metabolism regulation, and cell death. Mitochondrial dysfunction is associated with many diseases, including cancers, aging, and neurodegenerative disorders. Consequently, developing methods for mitochondrial regulation and treating related diseases has garnered significant interest in biological and medical research. Here, a smart framework nucleic acid (FNA) strategy is presented for mitochondrial interference and targeted cell elimination. Our approach involves the design of tetrahedral DNA nanostructures (TDNs) modified with triphenylphosphine and single‐stranded DNA sequences responding to specific nucleic acid biomarkers (e.g., microRNAs) presented in target cells. The interlinked DNA networks, formed in situ responding to specific biomarkers, enable targeting and enveloping of the mitochondria, leading to mitochondrial fragmentation and dysfunction. It is demonstrated that TDN‐based FNAs targeted the cancer‐associated microRNA (miR‐21) may enhance the efficacy of cancer therapy by disrupting mitochondrial function, while also serving as carriers of anti‐cancer drugs to reduce the side effects. Additionally, FNAs targeting the senescence‐associated microRNA (miR‐34a) specifically eliminate senescent cells in both cell and Caenorhabditis elegans models, thereby improving overall cell viability within mixed cell populations. This programmable and functionalized TDN‐based platform opens new avenues for advancing anti‐aging research and treating various diseases by achieving targeted cell elimination through mitochondrial interference.