Abstract
Safety and efficiency remain the critical hurdles hindering the practical application of gene agents, even though great effort has been made to develop various gene carriers. Herein, we present a novel biodegradable cancer therapeutic system based on DNA nanoflowers (DNFs) for targeted dual gene silencing. The therapeutic system was constructed by copying a rolling circle amplification template to produce long single-stranded DNAs with cell targeting and dual gene-silencing capability. The structure of the DNFs collapsed at acidic pH due to the decomposition of the co-assembled magnesium pyrophosphate, generating Mg2+ ions that act as cofactors for the DNAzymes and increase their ability to recognize and cleave target mRNAs. In vitro and in vivo studies demonstrated that the multifunctional DNFs showed promise for targeted cancer cell recognition, gene silencing, induction of apoptosis and inhibition of tumor growth. Considering the enhanced therapeutic effect and biocompatibility of this therapeutic platform, it is anticipated to be of great interest for the clinical treatment of cancers.
Highlights
Remarkable advances have been made in the diagnosis and treatment of cancer in light of the ever-increasing incidence of cancer over the past few decades
Construction and characterization of the DNA nanoflowers (DNFs) To validate our assumption, a long linear single-stranded DNA (ssDNA) encoding the complementary sequence of the AS1411 aptamer, the early growth response-1 (EGR-1) DNAzyme and the survivin DNAzyme was used to prepare a closed circular template for rolling circle amplification (RCA) (Figure 1 and Supplementary Figure S1), which has been recognized as a powerful tool to produce long ssDNA molecules with multiple functions
Cyclization of the ssDNA template and RCA products was confirmed by agarose gel electrophoresis (Supplementary Figure S2a)
Summary
Remarkable advances have been made in the diagnosis and treatment of cancer in light of the ever-increasing incidence of cancer over the past few decades. Gene therapy is recognized as a promising strategy for treating cancer.[1,2] The goal of targeted gene therapy is the downregulation of genes that contribute to cancer progression, and to selectively and inhibit tumor growth with minimal adverse side effects on normal cells.[3] Recently, ribozymes, deoxyribozymes (DNAzymes), antisense oligonucleotides and short interfering RNAs have been actively investigated due to their potential application in gene inactivation or downregulation.[4,5,6] Among these therapeutic agents, DNAzymes, which can be engineered to bind to complementary sequences in a target messenger RNA (mRNA) and cleave it at predetermined phosphodiester linkages, are attractive due to their easy, low-cost synthesis, high selectivity and significant catalytic efficiency.[7,8,9] Despite the increasing interest in DNAzyme-mediated gene silencing as a therapeutic strategy, safety and efficiency remain the critical hurdles to overcome for practical applications. It is highly desirable to develop a safe and biodegradable multigene-silencing system for efficient cancer therapy
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