In situ microRNA-triggered self-assembled nano-lanterns with confinement effect for imaging-guided dual-enhanced gene therapy

This is the authors' abstract. We don't add key points for this paper.

Single-stranded DNAzymes, as gene-silencing agents, are often indiscriminately taken up by both tumor and normal cells, resulting in toxicity to healthy tissues and reduced therapeutic efficacy. To address this challenge, we designed in situ self-assembled nano-lanterns with a confinement effect, triggered by microRNA (miRNA), for imaging-guided dual-enhanced gene therapy. This approach uses hairpin DNA monomers that are specifically activated by miRNA (miR-25-3p) overexpressed in tumor cells, initiating a hybridization chain reaction (HCR) to spontaneously assemble into extensive tandem arrays of DNAzymes. This self-assembly promotes the aggregation and confinement of DNAzymes, thereby increasing their local concentration and enhancing the cleavage efficiency of VEGFR2 mRNA. Additionally, the consumption of miR-25-3p during nano-lanterns assembly contributes to further regulation of VEGFR2 gene expression. Consequently, this synergistic mechanism inhibits VEGFR2 expression through both efficient VEGFR2 mRNA cleavage and miR-25-3p depletion, enabling dual-enhanced gene therapy with minimal side effects. In an anti-tumor experiment, tumor weight in mice was reduced by 84.5% compared to the PBS-treated group, with no observed side effects. In summary, the DNA nano-lanterns triggered by miR-25-3p enable dual-enhanced gene regulation therapy without significant side effects.