Magnesium-Stabilized Multifunctional DNA Nanoparticles for Tumor-Targeted and pH-Responsive Drug Delivery

Abstract

Functional nucleic acids, which can target cancer cells and realize stimuli-responsive drug delivery in tumor microenvironment, have been widely applied for anticancer chemotherapy. At present, high cost, unsatisfactory biostability, and complicated fabrication process are the main limits for the development of DNA-based drug-delivery nanocarriers. Here, a doxorubicin (Dox)-delivery nanoparticle for tumor-targeting chemotherapy is developed taking advantage of rolling circle amplification (RCA) technique, by which a high quantity of functional DNAs can be efficiently collected. Furthermore, Mg, a major electrolyte in human body showing superior biocompatibility, can sufficiently condense the very long sequence of an RCA product and better preserve its functions. The resultant DNA nanoparticle exhibits a high biostability, making it a safe and ideal nanomaterial for in vivo application. Through cellular and in vivo experiments, we thoroughly demonstrate that this kind of Mg-stabilized multifunctional DNA nanoparticles can successfully realize tumor-targeted Dox delivery. Overall, exploiting RCA technique and Mg condensation, this new strategy can fabricate nanoparticles with a nontoxic composition through a simple fabrication process and provides a good way to preserve and promote DNA functions, which will show a broad application potential in the biomedical field.

Hydrophobic Interaction: A Promising Driving Force for the Biomedical Applications of Nucleic Acids

“…[44,46] According to our investigations, other than MgPPi, the addition of an appropriate concentration of Mg 2+ could also condense the RCA product and induce the formation of a similar DNA structure with biostability against enzymatic degradation. [21] The RCA nanoparticles condensed by excessive Mg 2+ showed a smaller size of ≈100 nm, which can still keep intact and stable after going through the desalting column. There are three critical factors for the condensation of the RCA products and the subsequent biomedical applications.…”

“…Our group employed the RCA method as mentioned above to fabricate targeted chemotherapy-based nanostructures. [21] First, a carefully designed template was replicated through an RCA reaction to yield a large quantity of lssDNAs with periodic sequences, and each repeat is comprised of an aptamer sequence with the ability to target cancer cells and a hairpin sequence for doxorubicin (Dox)-loading and pH-responsive release ( Figure 3A,B). After that, a certain concentration of Mg 2+ could effectively cause the firm condensation of the lssDNA due to the hydrophobic interaction, forming nanoparticles with a small size of ≈100 nm (Mg-RNC).…”

“…3) The coordinative or electrostatic interactions between the nucleobases/phosphate backbones of DNAs and metal ions provide another approach to fabricate functional DNA-metal hybrid nanomaterials. [21] On the one hand, the DNA sequences act as nucleation sites and the stabilizing ligands for metal nanoparticles. On the other hand, the metal components will endow more functionalities to the DNA-metal hybrid nanomaterials, promoting their applications in the biological/chemical detecting, cellular and in vivo imaging, and therapeutics.…”

Circular Nucleic Acids: Discovery, Functions and Applications

“…In 2013, Tan and Zhao independently reported the self‐assembly of multivalent aptamer nanoflowers generated by RCA to load doxorubicin for targeted anticancer drug delivery and cell imaging. The nanoflowers were self‐assembled through metal ion‐mediated dense packaging and found to be readily size‐tunable, exceptionally resistant to exonuclease degradation, and able to circumvent multidrug resistance . These multivalent aptamers can also be incorporated with reduced graphene oxide, magnetic beads, FRET (fluorescent resonance energy transfer)‐based fluorescence molecules, or ferrocene (Figure C) for enhanced drug loading, efficient drug‐releasing or multiplexed cell imaging.…”

Rationally Designed DNA Nanostructures for Drug Delivery

“…Thus, previous intercalated drugs are released in response to environmental pH. Functionalized with aptamers, the resultant drug-carrier system accomplishes in vivo targeted delivery, and pH-stimulated sustained release of Dox ( Figure 5D) (Zhao et al, 2018).…”