Ribozyme–Spherical Nucleic Acids

Abstract

Ribozymes are highly structured RNA sequences that can be tailored to recognize and cleave specific stretches of mRNA. Their current therapeutic efficacy remains low due to their large size and structural instability compared to shorter therapeutically relevant RNA such as small interfering RNA (siRNA) and microRNA (miRNA). Herein, a synthetic strategy that makes use of the spherical nucleic acid (SNA) architecture to stabilize ribozymes and transfect them into live cells is reported. The properties of this novel ribozyme SNA are characterized in the context of the targeted knockdown of O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein involved in chemotherapeutic resistance of solid tumors, foremost glioblastoma multiforme (GBM). Data showing the direct cleavage of full-length MGMT mRNA, knockdown of MGMT protein, and increased sensitization of GBM cells to therapy-mediated apoptosis, independent of transfection agents, provide compelling evidence for the promising properties of this new chemical architecture.

Enzymatically Ligated DNA–Surfactants: Unmasking Hydrophobically Modified DNA for Intracellular Gene Regulation

“…One class of materials that has been particularly effective at delivering native nucleic acids are those that adopt spherical, outward‐facing orientations of oligonucleotides, such as the spherical nucleic acid (SNA) structures developed by Mirkin and co‐workers . Such assemblies have benefited the delivery of DNAzymes and ribozymes without the need for traditional cationic transfection agents. This was shown to be due to the formation of a densely coated layer of oligonucleotides arranged at a colloidal surface .…”

Robust and Tumor-Environment-Activated DNA Cross-Linker Driving Nanoparticle Accumulation for Enhanced Therapeutics

“…Functional DNA is a promising candidate as a nanoparticle cross-linker, due to its sensitive response to environmental variations, superior biocompatibility, and accessible chemistry for surface modification. 14,15 Cytosine-rich DNA strands can sensitively recognize acidic pH and fold into a quadruplex structure (i-motif structure) through CH + •C interactions. 16,17 The pH identification range of the i-motif forming strand (IFS) can be regulated by these sequences.…”

Ribbon of DNA Lattice on Gold Nanoparticles for Selective Drug Delivery to Cancer Cells

“…[8] Consequently,S NAsh ave been widely evaluated for various applications ranging from in vivo diagnostics to targeted therapies. [9,10] One drawback of SNAs,h owever, is their inability to be selectively taken up by diseased cells.F or this reason, SNAs are often conjugated with cell-specific recognition elements,s uch as antibodies [8c, 11] or aptamers, [12,13] to increase the selectivity of their uptake by diseased cells.These advances motivated us to synthesize Au-RDL2 composites and examine their ability for targeted drug delivery to cancer cells,which constituted the objective of the remaining experiments. [14][15][16] Thei nclusion of the two straightening strands in RDL2 was set up well for introducing functional entities,such as cancer-cell-recognizing aptamers for targeted delivery,o r reporting moieties for tracking the location of the Au-RDL2 particles.A S1411, aD NA aptamer that specifically recog-nizes nucleolin, which is often overexpressed on the surface of cancer cell lines, [17] was chosen for cancer-cell targeting.…”