100
Z. Liu and Y. Liu
photo-crosslinking into aptamer-functionalized nanoassembly structure. The DNA
nanoassembly with high leukemia cells specificity could effectively inhibit Pglycoprotein (P-gp) expression and reduce drug resistance. Using similar Y-shaped
DNAs as the basic unit, Zhang et al. [113] applied a controllable step-by-step selfassembly process to fabricate aptamer-based DNA dendritic nanostructures, which
carried DNA aptamers, anticancer drugs, and fluorophores (Fig. 4.8b). The DNA
dendrimers featured with high selectivity, excellent biocompatibility and biostability
as well as efficient cell internalization. Besides, each dendrimer enabled the incorporation of multiple aptamers to form a multivalent aptamer platform, therefore,
holding great potential in targeted cancer therapy.
In 2016, Li et al. fabricated a protein-DNA hybrid hydrogel assembled by three
types of streptavidin (SA)-based DNA tetrad (Y1-SA, Y2-SA, Y3-SA) [114]. Y2 and
Y3 were partially complementary with Y1 that was ATP aptamer. MUC1 aptamer
modification endowed the DNA hydrogel with tumor-targeting ability, and DOX was
embedded into GC base pairs of DNA hydrogel. After the cellular uptake of hydrogel
by tumor cells, the Y1 bound to ATP in microenvironment with high ATP concentration, causing the hydrogel to collapse and release DOX. With the aid of MUC1
aptamer for targeting cancer cell and ATP aptamer for accelerating drug release,
the DNA hydrogel-based drug delivery system showed enhanced cellular internalization and anti-cancer efficiency. Very recently, DNA nanocockleburs containing
AS1411 aptamer-decorated DNA cross units were constructed for effective targeted
delivery of DOX [115]. The experimental results showed that the Apt-nanocockleburs
exhibited higher cell uptake and increased cytotoxicity to MCF-7 cells than DNA
nanocockleburs without aptamer modification. Generally, there are multiple overexpressed proteins in cancer cells, so multiple aptamer modification is a common
strategy to improve the precise targeting ability of drug delivery systems. In another
study, Wei et al. [116] reported a DNA-based and aptamer-guided multifunctional
system, which combined targeting ligand, immuno-stimulation, and chemotherapy
into one platform, for enhanced and harmless antitumor therapy (Fig. 4.8c). The
CpG-MUC1-hydrogel nanoparticles were directly self-assembled from CpG, i-motif,
and MUC1 aptamer functional DNA sequences. S1–S4 DNA sequences served as
the cross-shaped DNA (C-DNA), and L1-L4 DNA sequences were the linkers. At
acidic conditions, the formation of i-motif quadruplex triggered the disassembly of CDNA, causing the destruction of CpG-MUC1-hydrogel/Dox nano-structure for DOX
release. After intravenous tail vein injection, MUC1 aptamer mediated the endocytosis of CpG-MUC1-hydrogel/DOX nanoparticles. Then, the hydrogel nanoparticles
dissociated in endo/lysosomes and released DOX for S-phase cell cycle arrest and
tumor cell apoptosis. The released CpG induced vast cytokine secretion from immune
cells which elicited potent host immune response to inhibit tumor cells.
Rolling circle amplification (RCA) recently emerges as an efficient approach
for synthesizing ultra-long DNA or RNA scaffold with repeated sequences. Wang
et al. [117] constructed a versatile self-sufficient DNAzyme-driven drug delivery
system containing Sgc8c aptamer and the rolling circle polymerized DNAzymesubstrate scafflolds (Fig. 4.8d). The long scafflolds self-assembled into flower-like
nanosponges for the encapsulation of pH-responsive ZnO nanoparticles. The full
Z. Liu and Y. Liu
photo-crosslinking into aptamer-functionalized nanoassembly structure. The DNA
nanoassembly with high leukemia cells specificity could effectively inhibit Pglycoprotein (P-gp) expression and reduce drug resistance. Using similar Y-shaped
DNAs as the basic unit, Zhang et al. [113] applied a controllable step-by-step selfassembly process to fabricate aptamer-based DNA dendritic nanostructures, which
carried DNA aptamers, anticancer drugs, and fluorophores (Fig. 4.8b). The DNA
dendrimers featured with high selectivity, excellent biocompatibility and biostability
as well as efficient cell internalization. Besides, each dendrimer enabled the incorporation of multiple aptamers to form a multivalent aptamer platform, therefore,
holding great potential in targeted cancer therapy.
In 2016, Li et al. fabricated a protein-DNA hybrid hydrogel assembled by three
types of streptavidin (SA)-based DNA tetrad (Y1-SA, Y2-SA, Y3-SA) [114]. Y2 and
Y3 were partially complementary with Y1 that was ATP aptamer. MUC1 aptamer
modification endowed the DNA hydrogel with tumor-targeting ability, and DOX was
embedded into GC base pairs of DNA hydrogel. After the cellular uptake of hydrogel
by tumor cells, the Y1 bound to ATP in microenvironment with high ATP concentration, causing the hydrogel to collapse and release DOX. With the aid of MUC1
aptamer for targeting cancer cell and ATP aptamer for accelerating drug release,
the DNA hydrogel-based drug delivery system showed enhanced cellular internalization and anti-cancer efficiency. Very recently, DNA nanocockleburs containing
AS1411 aptamer-decorated DNA cross units were constructed for effective targeted
delivery of DOX [115]. The experimental results showed that the Apt-nanocockleburs
exhibited higher cell uptake and increased cytotoxicity to MCF-7 cells than DNA
nanocockleburs without aptamer modification. Generally, there are multiple overexpressed proteins in cancer cells, so multiple aptamer modification is a common
strategy to improve the precise targeting ability of drug delivery systems. In another
study, Wei et al. [116] reported a DNA-based and aptamer-guided multifunctional
system, which combined targeting ligand, immuno-stimulation, and chemotherapy
into one platform, for enhanced and harmless antitumor therapy (Fig. 4.8c). The
CpG-MUC1-hydrogel nanoparticles were directly self-assembled from CpG, i-motif,
and MUC1 aptamer functional DNA sequences. S1–S4 DNA sequences served as
the cross-shaped DNA (C-DNA), and L1-L4 DNA sequences were the linkers. At
acidic conditions, the formation of i-motif quadruplex triggered the disassembly of CDNA, causing the destruction of CpG-MUC1-hydrogel/Dox nano-structure for DOX
release. After intravenous tail vein injection, MUC1 aptamer mediated the endocytosis of CpG-MUC1-hydrogel/DOX nanoparticles. Then, the hydrogel nanoparticles
dissociated in endo/lysosomes and released DOX for S-phase cell cycle arrest and
tumor cell apoptosis. The released CpG induced vast cytokine secretion from immune
cells which elicited potent host immune response to inhibit tumor cells.
Rolling circle amplification (RCA) recently emerges as an efficient approach
for synthesizing ultra-long DNA or RNA scaffold with repeated sequences. Wang
et al. [117] constructed a versatile self-sufficient DNAzyme-driven drug delivery
system containing Sgc8c aptamer and the rolling circle polymerized DNAzymesubstrate scafflolds (Fig. 4.8d). The long scafflolds self-assembled into flower-like
nanosponges for the encapsulation of pH-responsive ZnO nanoparticles. The full