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References 31
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37
3
Framework Nucleic Acid-Based Nanomaterials: A Promising
Vehicle for Small Molecular Cargos
Yanjing Li
Tianjin Medical University School and Hospital of Stomatology, Department of Prosthodontics, 12 Qixiangtai Road,
Tianjin 300070, PR China
The biological polymer DNA carries information about life and stores genetic codes in
living organisms. DNA is constructed from four basic blocks, including guanine (G),
cytosine (C), adenine (A), and thymine (T), and is assembled through Watson–Crick
base-pairing. In 1982, Prof. Seeman pioneered specic DNA architectures through rigid
junctions [1], thus leading to the development of DNA nanotechnology. Thereafter, great
progress has been made in the construction, modication, and application of nucleic
acid nanomaterials. A variety of nucleic acid nanomaterials have been constructed, from
DNA Holliday junctions to two-dimensional crystalline structures [2], two-dimensional
nanogrids [3], advanced DNA origami [4], and DNA tetrahedra [5].
Among these architectures, framework nucleic acids (FNAs), which include DNA nanos-
tructures such as DNA origami, tetrahedra, and polyhedra, have been widely researched
and applied in the biomedical eld because of their controllable structure, rapid assembly,
and high yield. In addition, FNAs demonstrate excellent physical and chemical properties
and biological characteristics and display a number of advantages in disease treatment,
drug delivery, and biosensing. First, based on the principle of complementary base pair-
ing, FNAs exhibit controlled self-assembly and excellent programmability [6]. According
to the desired requirements, FNAs with dierent sizes, shapes, and chiral nanostructures
can be constructed via specic designs. It is to be noted that the small size of these nanos-
tructures leads to passive targeting properties and wide distribution in organisms, which
facilitates certain delivery strategies. Furthermore, functional nucleic acid fragments can
be connected to the ends of single-stranded DNA (ssDNA) through sequence lengthening
or sticky ends, such as targeted aptamers. Second, the spatial arrangement between each
successive base pair provides abundant sites for the insertion of small molecules, which
is benecial for the ecient loading and delivery of small molecular cargo. Third, FNAs
possess excellent biocompatibility and biodegradability, low immunogenicity [7], and rela-
tive structural stability [8], which are essential for ideal drug carriers. Fourth, unlike linear
nucleic acids, FNAs have unique interactions with cells, such as remarkable cell mem-
brane penetrability and regulation of cell behavior [6]. It is dicult for ssDNA to enter cells
directly, whereas FNAs can enter cells without the help of transfection agents, which may
Nucleic Acid-Based Nanomaterials: Stabilities and Applications, First Edition.
Edited by Yunfeng Lin and Shaojingya Gao.
© 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.
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38 3 Framework Nucleic Acid-Based Nanomaterials: A Promising Vehicle for Small Molecular Cargos
be because of the unique spatial structure of the latter. Spontaneous cellular internalization
can ensure the ecient entry of the loaded cargo into the cell, and the biological eect of
FNAs and cargos may act synergistically through a pleiotropic mechanism.
Based on these merits, FNAs are regarded as ideal carriers of small molecular agents that
can overcome the typical limitations of using these agents in clinical applications, such as
poor stability in the physiological environment, low targetability, low cell uptake eciency,
and undesired high o-target toxicity. Therefore, FNAs have gradually become a research
hotspot in the eld of small-molecule transport. Here, we summarize the current status of
FNAs for the delivery of small molecules. This review focuses on the classication, syn-
thesis, and properties of FNAs and emphasizes their potential in various strategies for the
delivery of small molecules, their biomedical applications, and the underlying mechanisms.
Finally, the prospects and challenges in the use of FNAs for drug delivery are discussed.
3.1 Basis of FNAs as Potential Drug Carriers
3.1.1 Classification and Construction of FNAs
FNAs include various architectures such as compact folded DNA origami, tetrahedral
or polyhedral DNA frameworks, and spherical DNA structures. DNA origami, one of
the widely researched FNAs, is a kind of self-assembled DNA nanostructure with a
precisely designed shape and size. DNA origami is constructed by folding a long ssDNA,
known as a “DNA scaold strand,” and introducing a set of short ssDNA, which binds
to the DNA scaold and acts as “staples” to hold nonarbitrary structures (Figure 3.1).
The DNA origami technique dates back to the pioneering work of Rothemund in 2006
[9]. After that seminal publication of Rothemund, hundreds of DNA origami structures
have been fabricated using this method, including two-dimensional structures such
as triangles, rectangles, ve-pointed stars, smiley-face circles [9], and crystals, as well
as three-dimensional structures such as nanotubes [10], nanocubes [11], honeycombs,
gridirons, wireframe nanopolyhedra, and polyhedral meshes [12]. Recently, scaold-free
structures [13], shape-complementary DNA components [13], and dynamic architectures
that can respond to stimuli have been developed. In Rothemund’s research, the ssDNA
scaold and staples were designed using a computer program that assists with manual
correction, and the origami structures were fabricated through DNA self-assembly in a
one-pot reaction. Using this approach, a series of nanoscale two-dimensional shapes have
been fabricated, including triangles, rectangles, stars, and combinations, as well as disks
with smiley-face holes, patterns representing letters, maps, and even Mona Lisa [14].
Based on the “bottom-up” self-assembly route, Douglas et al. improved the design program
and developed a graphical interface-based design program named caDNAno to save time
and reduce errors in origami design [15]. They subsequently extended the one-spot DNA
origami method to build custom three-dimensional structures [16], such as a 10-layer
monolith, a square nut with a hexagonal tunnel, and a stacked cross consisting of two
domains. Moreover, a larger structure, icosahedral wireframe DNA origami, has also been
constructed using a two-step hierarchical assembly method [16]. Gradually, this technique
has been generalized to DNA origami fabrication, where these architectures have played a
prominent role in the biomedical eld because of their precisely controllable dimensions,
shapes, and sizes.
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3.1 Basis of FNAs as Potential Drug Carriers 39
Scaffold
Staples
Origami folding
ssDNA
One-pot annealing
DNA apex
3-way junction
Fabrication
Groove
intercalation
Electrostatic
interaction
Drug
loading
Chemical
binding
Base pair
intercalation
Electrostatic interaction
/chemical binding
(Peptide, Fluorophore
Cationic polymer)
Sequence extending
(Aptamer, RNA)
Cell
Membrane
Blood-Brain
Barrier
Modication
Characteristics
Barrier crossing
Framework nucleic acids
Figure 3.1 The fabrication and properties of FNAs that are suitable for the delivery of small
molecules.
Another widely researched FNA is the DNA tetrahedron, which is the simplest poly-
hedron. Tetrahedrons, including DNA and RNA tetrahedrons, are a family of wireframe
structures with lengths of approximately 10 nm on a side and are assembled using a few
ssDNAs. The fabrication of DNA tetrahedrons can be traced back to 2005, when Good-
man’s team designed a family of DNA tetrahedrons by using four ssDNAs through one-pot
annealing [5]. The synthesized tetrahedron possesses a high assembly yield (∼95%), exi-
ble junctions in the vertices, and a rigid structure that is capable of resisting deformation.
A single tetrahedron can act as a block for assembling larger constructs via programmable
DNA linkers and is assembled via a rapid process. Hence, DNA tetrahedra have been widely
studied in the biomedical eld, paving the wayfor the development and application of tetra-
hedral FNAs (tFNAs). DNA tetrahedrons can also be fabricated using other methods. In
contrast to the method used by Ge et al., DNA tetrahedrons have been formed by four DNA
triplexes. The DNA triplex has a sticky end such that four triplexes can interact with each
other to form a tetrahedron [17]. Three-way-junction hybridization is generally used for the
fabrication of DNA polyhedra, enabling the formation of large structures. Nevertheless, this
process is hampered by cost and yield [18]. Veneziano et al. introduced a DNA wireframe
design procedure, DAEDALUS, and constructed a DNA tetrahedron using a scaold and a
set of staples via the origami approach [19]. Compared with one-pot annealing, the scaold
folding method can be used to construct larger and more rigid DNA tetrahedrons. How-
ever, this approach is expensive and is only applicable to large structures. Therefore, owing
to their structural simplicity, simple synthesis procedure, and high yield, DNA tetrahedra
fabricated via one-pot annealing have been widely researched and applied.
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40 3 Framework Nucleic Acid-Based Nanomaterials: A Promising Vehicle for Small Molecular Cargos
Based on precise design, FNAs can be contrasted with other polyhedrons, such as hex-
ahedron, octahedron, cuboctahedron, icosahedron, and zonohedron, as well as spherical,
bioinspired, and arbitrary structures [19, 20]. Nonetheless, research on these architectures
in the biomedical eld, especially drug delivery, and their application is scant.
3.1.2 Physical and Chemical Properties
FNAs oer several advantages that make them suitable for the delivery of small molecules
and provide multiple binding choices. First, the spaces between the base pairs and grooves
in DNA double helices provide an interspace for the intercalation of small molecules [21].
The interaction and binding anity between drugs and DNA nanostructures depend on the
DNA topology and groove dimensions. Second, FNAs possess a negative charge, which is
benecial for binding positively charged drugs via electrostatic interactions. Third, because
of the abundant freeresidues in DNA bases, FNAs can carry small molecules through chem-
ical cross-linking, such as hydrogen bonding. Fourth, self-assembled FNAs are exible and
editable and can be connected to the edge or vertices of the backbone through sequence
extension or via the sticky ends, endowing FNAs with functionality and targeting ability,
while enabling visual monitoring, to meet the requirements of dierent drug delivery
systems. The quality and eciency of the modications of FNAs can be precisely controlled
owing to the exact localization of nucleic acids. Consequently, FNAs exhibit relative struc-
tural stability both in vitro and in vivo [22]. Under storage conditions, that is, in a buer
containing magnesium ions, at constant pH, and at low temperature, FNAs can remain
stable for several days or even weeks without polymerization or degradation. In biological
environments, FNAs are exposed to low cation concentrations, variable pH, and active
DNA-degrading enzymes, and their structural integrity can persist for hours or several
days. However, compared to double-stranded DNA, FNAs are more resistant to DNase, and
the degradation rate is dependent on the structure of the FNAs. For instance, closely packed
structures can be degraded more slowly [23]. In addition, modications with lipid bilayers,
proteins, or cationic polymers can protect FNAs from DNase digestion, enhancing their
stability and function under physiological conditions [24–26]. Finally, with the advantages
of precise design and sophisticated manufacturing, the dimension and shape of FNAs can
be controlled, aording specic vectors for the delivery and application of dierent drugs.
3.1.3 Biological Properties
Owing to their excellent biocompatibility and biodegradability, rapid and autonomous
endocytosis, and extensive intracellular distribution, FNAs have been widely used in the
eld of drug delivery. Moreover, DNA is an essential molecule for life and can be degraded
by active nucleases in vivo. Therefore, the nature of DNA endows FNAs with tremendous
biosafety. Biocompatibility is an essential characteristic of carriers. Although many
currently researched nanocarriers can eciently improve the bioavailability and biological
eects of cargos, their poor biocompatibility and biodegradability hamper their in-depth
research and application. Therefore, FNAs provide valuable advantages for drug delivery.
FNAs are more readily endocytosed compared to ssDNA. FNAs can rapidly enter
cells in large quantities without the help of transfection agents and can retain their
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