Targeted Delivery of DNA Framework-Encapsulated Native Therapeutic Protein into Cancer Cells

A protein-based therapy is significantly challenged by the successful delivery of native proteins into the targeted cancer cells. We address this challenge here using an all-sealed divalent aptamer tetrahedral DNA framework (asdTDF) delivery platform, in which the protein drug is encapsulated inside the cavity of the framework stoichiometrically via a reversible chemical bond. The ligase-assisted seal of the nicks results in highly enhanced TDF stability of the against nuclease digestion to effectively protect the therapeutic protein from degradation. In addition, the divalent aptamer sequences incorporated into the framework favor it with a target-specific and efficient delivery capability. Importantly, upon being readily delivered into the targeted cancer cells, endogenous glutathione can trigger the release of the native therapeutic protein from the TDF in a traceless fashion by cleaving the reversible chemical bond, thereby leading to effective apoptosis of the specific cancer cells.