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 H 2 O 2 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 *

Polymeric micelles have received increased attention in the field of pharmaceutical exploitation. However, supra-100-nm micelles, suitable for the EPR effect, cannot penetrate through the dense collagen matrix in solid tumor tissues, thus decreasing the efficacy of anticancer agents. In this work, amphiphilic nucleic acid polymers with tunable hydrophobicity were designed, and size-tunable nucleic acid assemblies were developed to resolve the conflict between EPR effect and spatially uniform penetration ability.

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