Engineering of Bioinspired, Size-Controllable, Self-Degradable Cancer-Targeting DNA Nanoflowers via the Incorporation of an Artificial Sandwich Base

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Abstract

In this article, we used an artificial DNA base to manipulate the formation of DNA nanoflowers (NFs) to easily control their sizes and functionalities. Nanoflowers have been reported as the noncanonical self-assembly of multifunctional DNA nanostructures, assembled from long DNA building blocks generated by rolling circle replication (RCR). They could be incorporated with myriad functional moieties. However, the efficacy of these DNA NFs as potential nanocarriers delivering cargo in biomedicine is limited by the bioavailability and therapeutic efficacy of their cargo. Here we report the incorporation of metal-containing artificial analogues into DNA strands to control the size and the functions of NFs. We have engineered bioinspired, size-controllable, self-degradable cancer-targeting DNA nanoflowers (Sgc8-NFs-Fc) via the incorporation of an artificial sandwich base. More specifically, the introduction of a ferrocene base not only resulted in the size controllability of Sgc8-NFs-Fc from 1000 to 50 nm but also endowed Sgc8-NFs-Fc with self-degradability in the presence of H₂O₂ via Fenton's reaction. In vitro experiments confirmed that Sgc8-NFs-Fc/Dox could be selectively taken up by protein tyrosine kinase 7 (PTK7)-positive cancer cells and subsequently cleaved via Fenton's reaction, resulting in rapid release kinetics, nuclear accumulation, and enhanced cytotoxicity of their cargo. In vivo experiments further confirmed that Sgc8-NFs-Fc has good tumor-targeting ability and could significantly improve the therapeutic efficacy of doxorubicin in a xenograft tumor model. On the basis of their tunable size and on-demand drug release kinetics upon H₂O₂ stimulation, the Sgc8-NFs-Fc nanocarriers possess promising potential in drug delivery.

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