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Derepression of co-silenced tumor suppressor genes by nanoparticle-loaded circular ssDNA reduces tumor malignancy

Circular ssDNA can sequester inhibitory microRNAs to restore tumor suppressor gene function, thereby inhibiting tumor progression. Protecting tumor suppressors Strategies to target inactive tumor suppressor genes in cancer lag behind advances in targeting oncogenes. In new work, Meng et al. developed a therapeutic strategy to simultaneously up-regulate three different tumor suppressor genes that are sometimes co-silenced in different cancers by a microRNA called miR-9. They created a circular single-stranded DNA (CSSD) containing sequences to bind miR-9, thus sequestering it away from its target tumor suppressor genes. Loading the CSSDs onto nanoparticles improved delivery into human tumor cells. The CSSD increased expression of the three tumor suppressor proteins and displayed an antitumor effect in both cell line–based ex vivo models and dozens of patient-derived xenografts in mice. The co-silencing of multiple tumor suppressor genes can lead to escalated malignancy in cancer cells. Given the limited efficacy of anticancer therapies targeting single tumor suppressor genes, we developed small circular single-stranded DNA (CSSD) that can up-regulate the expression of co-silenced tumor suppressor genes by sequestering microRNAs (miRNAs) that negatively regulate these genes. We found that cancer patients with low tumor expression of the tumor suppressor genes KLF17, CDH1, and LASS2 had shortened survival times. The up-regulation of these genes upon transfection of artificial CSSD-9 inhibited tumor proliferation and metastasis and promoted apoptosis in vitro as well as in ex vivo and patient-derived xenograft models. In addition, CSSD is more stable and effective than current miRNA inhibitors, and transfecting CSSDs via nanoparticles substantially improved delivery efficiency. The use of a single CSSD can promote the inhibition of multiple tumor suppressor genes. This study provides evidence for the possibility of using CSSDs as therapeutic miRNA inhibitors to target the co-silencing of multiple tumor suppressor genes.