Coating tetrahedral DNA framework with endosomolytic peptides for improved stability and cytosolic delivery

DNA nanostructures have emerged as promising carriers for drug delivery. However, challenges such as low stability, poor cellular uptake efficiency, and vulnerability to lysosomal degradation still hinder their therapeutic potential. In this study, we demonstrate the coating of tetrahedral DNA frameworks (TDF) with the endosomolytic peptide L17E through electrostatic interactions to address these issues. Our findings highlight that L17E coating substantially enhances the stability of TDFs and improves their uptake efficiency into RAW264.7 cells through endocytosis and macropinocytosis. Moreover, L17E coating enables efficient endosomal release of TDFs. Finally, we employed L17E-coated TDF to deliver osteogenic growth peptide and demonstrated its potential applications in inhibiting periodontitis both in vitro and in vivo. This straightforward and cost-effective strategy holds promise for advancing the biomedical applications of DNA nanostructures.