Nucleic Acid Base Pairs Research Articles

BasePairPuzzle: Molecular Models for Manipulating the Concept of Hydrogen Bonds and Base Pairs in Nucleic Acids

The use of molecular models in chemistry and biochemistry classes is very effective in helping students understand covalent bonds and the chemical structure of molecules. However, conventional molecular models cannot represent intermolecular interactions such as hydrogen bonds and electrostatic interactions. Herein, we describe 3D printed molecular models of nucleobases with the S and N poles of neodymium magnets placed as the donor and acceptor atoms of hydrogen bonds, respectively. The molecular models, called BasePairPuzzle, allow the user to experience manually how molecular recognition occurs when molecules attract or repel each other. This helps to understand the concept of hydrogen bonding and electrostatic interactions. By playing with two or more molecular parts, by attaching and detaching them, users can understand and realize various biological phenomena at the molecular level, such as why DNA forms complementary A–T and G–C base pairs to store genetic information, how DNA mutations can occur, and how nucleic acids can form various noncomplementary base pairs to have complex structures and functions other than storing and transmitting genetic information. In addition, for professional research scientists, the molecular models can support the discovery of new molecular design ideas in drug discovery and nanotechnology.

A Density Functional Theory and Information-Theoretic Approach Study of Interaction Energy and Polarizability for Base Pairs and Peptides.

Using density functional theory (DFT) and the information-theoretic approach (ITA) quantities to appreciate the energetics and properties of biopolymers is still an unaccomplished and ongoing task. To this end, we studied the building blocks of nucleic acid base pairs and small peptides. For base pairs, we have dissected the relative importance of energetic components by using two energy partition schemes in DFT. Our results convincingly show that the exchange-correlation effect predominantly governs the molecular stability of base pairs while the electrostatic potential plays a minor but indispensable role, and the steric effect is trivial. Furthermore, we have revealed that simple density-based ITA functions are in good relationships with molecular polarizabilities for a series of 30 hydrogen-bonded base pairs and all 20 natural α-amino acids, 400 dipeptides, and 8000 tripeptides. Based on these lines, one can easily predict the molecular polarizabilities of larger peptides, even proteins as long as the total molecular wavefunction is available, rather than solving the computationally demanding coupled-perturbed Hartree–Fock (CPHF) equation or its DFT counterpart coupled-perturbed Kohn–Sham (CPKS) equation.

DNA Base Pairing-Inspired Supramolecular Nanodrug Camouflaged by Cancer-Cell Membrane for Osteosarcoma Treatment.

Osteosarcoma (OS) is one of the most common bone malignant tumors which mainly develops in adolescents. Although neoadjuvant chemotherapy has improved the prognosis of patients, numerous chemotherapeutic challenges still limit their use. Here, inspired by the Watson-Crick base pairing in nucleic acids, hydrophobic (methotrexate) and hydrophilic (floxuridine) chemo-drugs are mixed and self-assembled into M:F nanoparticles (M:F NPs) through molecular recognition. Then, the obtained NPs are co-extruded with membranes derived from OS cells to form cancer-cell membrane-coated NPs (CCNPs). With protected membranes at the outer layer, CCNPs are highly stable in both physiological and weak acid tumor conditions and possess homologous tumor targeted capability. Furthermore, the proteomic analysis first identifies over 400 proteins reserved in CCNPs, most of them participatingin tumor cell targeting and adhesion processes. In vitro studies reveal that CCNPs significantly inhibit the PI3K/AKT/mTOR pathway, which promotes cell apoptosis and cell cycle arrest. More importantly, cell membrane camouflage significantly prolongs the circulation half-life of CCNPs, elevates the drug accumulation at tumor sites, and promotes anti-tumor efficacy in vivo. As a convenient and effective strategy to construct a biomimetic NP with high drug loading ratio, the CCNPs provide new potentials for precise and synergistic antitumor treatment.

From Molecular to Cluster Properties: Rotational Spectroscopy of 2-Aminopyridine and of Its Biomimetic Cluster with Water

We report the observation and analysis of the rotational spectrum of a 1:1 cluster between 2-aminopyridine and water (AMW) carried out with supersonic expansion Fourier transform microwave spectroscopy at 4.7–16.5 GHz. Measurements of the 2-aminopyridine monomer (AMP) were also extended up to 333 GHz for the room-temperature rotational spectrum and to resolved hyperfine splitting resulting from the presence of two 14N quadrupolar nuclei. Supersonic expansion measurements for both AMP and AMW were also carried out for two synthesized isotopic species with single deuteration on the phenyl ring. Nuclear quadrupole hyperfine structure has also been resolved for AMW and the derived splitting constants were used as an aid in structural analysis. The structure of the AMW cluster was determined from the three sets of available rotational constants and the hydrogen bonding configuration is compared with those for clusters with water of similarly sized single-ring molecules. Experimental results aided by quantum chemistry computations allow the conclusion that the water molecule is unusually strongly bound by two hydrogen bonds, OH...N and O...HN, to the NCNH atomic chain of AMP with the potential to replace hydrogen bonds to the identical structural segment in cytosine and adenine in CT and AT nucleic acid base pairs.

Effect of Ectoine on the Conformation and Hybridization of dsDNA in Monolayer Films: A Spectroelectrochemical Study

AbstractLack of long‐time stability of dsDNA‐based supramolecular assemblies is an important issue that hinders their applications. In this work, 20 base pairs long dsDNA fragments [(dCdG)20‐65 %] composed of 65 % dCdG and 35 % dAdT nucleotides were tethered via a thiol to the surface of a gold electrode. The self‐assembled (dCdG)20‐65 % monolayer was immersed in solutions containing ectoine, a compatible solute. Electrochemical results showed that these monolayers were stable for one month. In situ IR spectroscopy indicated that ectoine interacts weakly with the phosphate‐ribose backbone, dehydrating the phosphate groups and stabilizing the A‐DNA conformation. This structural reorganization led to a reorientation of nucleic acid base pairs and a local disruption of the double‐helix structure. However, the conformation and orientation of the dsDNA fragment was stable in the −0.4<E<0.3 potential range. As a direct interaction between ectoine and dsDNA, the enzymatic reaction of exonuclease VII hydrolyzing the ester phosphate bond in ssDNA, was blocked. We show that the addition of a compatible solute to the electrolyte solution stabilized the dsDNA structure despite structural rearrangements.

Enzymatic construction of metal-mediated nucleic acid base pairs.

Artificial metal base pairs have become increasingly important in nucleic acids chemistry due to their high thermal stability, water solubility, orthogonality to natural base pairs, and low cost of production. These interesting properties combined with ease of chemical and enzymatic synthesis have prompted their use in several practical applications, including the construction of nanomolecular devices, ions sensors, and metal nanowires. Chemical synthesis of metal base pairs is highly efficient and enables the rapid screening of novel metal base pair candidates. However, chemical synthesis is limited to rather short oligonucleotides and requires rather important synthetic efforts. Herein, we discuss recent progress made for the enzymatic construction of metal base pairs that can alleviate some of these limitations. First, we highlight the possibility of generating metal base pairs using canonical nucleotides and then describe how modified nucleotides can be used in this context. We also provide a description of the main analytical techniques used for the analysis of the nature and the formation of metal base pairs together with relevant examples of their applications.

3D Heteronuclear Magnetization Transfers for the Establishment of Secondary Structures in SARS-CoV-2-Derived RNAs.

Multidimensional NOESY experiments targeting correlations between exchangeable imino and amino protons provide valuable information about base pairing in nucleic acids. It has been recently shown that the sensitivity of homonuclear correlations involving RNA’s labile imino protons can be significantly enhanced, by exploiting the repolarization brought about by solvent exchanges. Homonuclear correlations, however, are of limited spectral resolution, and usually incapable of tackling relatively large homopolymers with repeating structures like RNAs. This study presents a heteronuclear-resolved version of those NOESY experiments, in which magnetization transfers between the aqueous solvent and the nucleic acid protons are controlled by selecting specific chemical shift combinations of a coupled 1H–15N spin pair. This selective control effectively leads to a pseudo-3D version of HSQC-NOESY, but with cross-peaks enhanced by ∼2–5× as compared with conventional 2D NOESY counterparts. The enhanced signal sensitivity as well as access to both 15N–1H and 1H–1H NOESY dimensions can greatly facilitate RNA assignments and secondary structure determinations, as demonstrated here with the analysis of genome fragments derived from the SARS-CoV-2 virus.

In Silico Investigation of Electronic Structure, Binding Patterns and Molecular Docking of Nevirapine: An anti-HIV Type-1 Drug

Nevirapine is used in the treatment of Human Immunodeficiency Virus Type 1 (HIV-1) infection. The structure of nevirapine belongs to the dipyridodiazepinone class of chemical. In the present work, molecular geometries of nevirapine drug, AU and GC base pairs have been optimized by DFT method with B3LYP/6-31G(d,p) basis set. The MEP and HOMO-LUMO surfaces have been scanned at 0.001 electron/Bohr3 isodensity surface. Further, HOMO-LUMO energies have been used to calculate ionization potential, electron affinity, electronegativity, global hardness and softness parameters of the drug molecule as well as AU and GC base pairs. IR and Raman spectra of the drug molecule have been analyzed in the light of standard data. Results obtained from NBO analysis have been analyzed in terms of the hybridization of atoms and electronic structure of drug molecule. Binding patterns of the drug molecule with nucleic acid base pairs (AU and GC) have been examined using second order perturbation theory valid at intermediate range. Efforts have been made to elucidate the chemical and biological properties of the drug. The inhibition activity of the drug molecule against HIV-1 reverse transcriptase (Y2NG) in complex with inhibitor GSK560 has been examined with the help of molecular docking. It has been observed that nevirapine prefers to bind in the guanine-cytosine rich region of nucleic acid helices. Further, there exists gross similarity between calculated vibrational assignment and the standard data as reported in the literature.

A Comprehensive Review on Fused Heterocyclic as DNA Intercalators: Promising Anticancer Agents.

Since the discovery of DNA intercalating agents (by Lerman, 1961), a growing number of organic, inorganic, and metallic compounds have been developed to treat life-threatening microbial infections and cancers. Fused-heterocycles are amongst the most important group of compounds that have the ability to interact with DNA. DNA intercalators possess a planar aromatic ring structure that inserts itself between the base pairs of nucleic acids. Once inserted, the aromatic structure makes van der Waals interactions and hydrogen-bonding interactions with the base pairs. The DNA intercalator may also contain an ionizable group that can form ionic interactions with the negatively charged phosphate backbone. After the intercalation, other cellular processes could take place, leading ultimately to cell death. The heterocyclic nucleus present in the DNA intercalators can be considered as a pharmacophore that plays an instrumental role in dictating the affinity and selectivity exhibited by these compounds. In this work, we have carried out a revision of small organic molecules that bind to the DNA molecule via intercalation and cleaving and exert their antitumor activity. A general overview of the most recent results in this area, paying particular attention to compounds that are currently under clinical trials, is provided. Advancement in spectroscopic techniques studying DNA interaction can be examined in-depth, yielding important information on structure-activity relationships. In this comprehensive review, we have focused on the introduction to fused heterocyclic agents with DNA interacting features, from medicinal point of view. The structure-activity relationships points, cytotoxicity data, and binding data and future perspectives of medicinal compounds have been discussed in detail.

Enzymatic Formation of an Artificial Base Pair Using a Modified Purine Nucleoside Triphosphate.

The expansion of the genetic alphabet with additional, unnatural base pairs (UBPs) is an important and long-standing goal in synthetic biology. Nucleotides acting as ligands for the coordination of metal cations have advanced as promising candidates for such an expansion of the genetic alphabet. However, the inclusion of artificial metal base pairs in nucleic acids mainly relies on solid-phase synthesis approaches, and very little is known about polymerase-mediated synthesis. Herein, we report the selective and high yielding enzymatic construction of a silver-mediated base pair (dImC-AgI-dPurP) as well as a two-step protocol for the synthesis of DNA duplexes containing such an artificial metal base pair. Guided by DFT calculations, we also shed light into the mechanism of formation of this artificial base pair as well as into the structural and energetic preferences. The enzymatic synthesis of the dImC-AgI-dPurP artificial metal base pair provides valuable insights for the design of future, more potent systems aiming at expanding the genetic alphabet.

Mutual Relations between Substituent Effect, Hydrogen Bonding, and Aromaticity in Adenine-Uracil and Adenine-Adenine Base Pairs.

The electronic structure of substituted molecules is governed, to a significant extent, by the substituent effect (SE). In this paper, SEs in selected nucleic acid base pairs (Watson-Crick, Hoogsteen, adenine-adenine) are analyzed, with special emphasis on their influence on intramolecular interactions, aromaticity, and base pair hydrogen bonding. Quantum chemistry methods—DFT calculations, the natural bond orbital (NBO) approach, the Harmonic Oscillator Model of Aromaticity (HOMA) index, the charge of the substituent active region (cSAR) model, and the quantum theory of atoms in molecules (QTAIM)—are used to compare SEs acting on adenine moiety and H-bonds from various substitution positions. Comparisons of classical SEs in adenine with those observed in para- and meta-substituted benzenes allow for the better interpretation of the obtained results. Hydrogen bond stability and its other characteristics (e.g., covalency) can be significantly changed as a result of the SE, and its consequences are dependent on the substitution position. These changes allow us to investigate specific relations between H-bond parameters, leading to conclusions concerning the nature of hydrogen bonding in adenine dimers—e.g., H-bonds formed by five-membered ring nitrogen acceptor atoms have an inferior, less pronounced covalent nature as compared to those formed by six-membered ring nitrogen. The energies of individual H-bonds (obtained by the NBO method) are analyzed and compared to those predicted by the Espinosa-Molins-Lecomte (EML) model. Moreover, both SE and H-bonds can significantly affect the aromaticity of adenine rings; long-distance SEs on π-electron delocalization are also documented.

Functional DNA Structures and Their Biomedical Applications

Since the discovery of the double-helix structure in 1953, nucleic acids have been developed from natural genetic codes into functional building blocks in a wide range of biotechnology and material...

Fast Scan Cyclic Voltammetry As a DNA Sensor Using Carbon Fiber Microelectrodes

Over the past five decades and since the discovery of the structure of nucleic acids (DNA and RNA), different technological advancements have been achieved to understand the overall biochemical properties of nucleic acids. The electrochemical reactivity of these nucleobases defines the overall reactivity of DNA. So far, technological progress on the development of electrochemical DNA biosensors has been applied on different biomedical and environmental analyses which includes, analysis of infectious diseases, diagnosis and treatment of cancer and extensive studies on neurodegenerative and genetic diseases. As nucleic acids are the profound and vital biomolecules of all living things, they are still the center of intensive research. The building blocks of DNA are purine bases, adenine and guanine and pyrimidine bases, thymine and cytosine, where each base is attached to the pentose sugar with phosphate group.Fast scan cyclic voltammetry (FSCV) is an electroanalytical technique which applies a voltage in a fast (greater than 400 V/s) and repeating manner to a working electrode and records the resultant current produced by oxidation of analyte at the electrode surface. Previous research by Venton and colleagues has shown that the electroactive nucleosides and nucleotides can be oxidized at a voltage of a specific waveform, using carbon fiber-microelectrode (CFME). The applied voltage can only oxidize specific nucleobases such as purines and the peak oxidative current is analyzed to quantify the concentration of the analyte.When co-detecting the purine nucleosides, the two primary oxidative peaks interfere with each other. As a result, a scalene waveform for the co-detection of adenosine and guanosine, initially developed by Ross et. al, was adapted to help with the co-detection of purine bases adenine and guanine in DNA. The used waveform sweeps up at 150 V/s from -0.4 to 1.45 V and sweeps back at 400V/s vs. a silver-silver chloride (Ag/AgCl) reference electrode. Adenine was recorded to have two oxidative peaks at 1.34 V on the backward scan (primary peak) and another at 1 V on the forward scan (secondary scan). The two peaks come from the oxidation of C2 and C8 into ketones. In addition, guanine was recorded to have two oxidative peaks at 1.2 V on the forward scan (primary peak) and another at 0.7 V on the backward scan (secondary peak). The two peaks are from the oxidation of C8 into a ketone and the oxidation of N7 after it has lost its hydrogen from the oxidation of C8. The structure of the DNA sample, (ssDNA, dsDNA, synthetic DNA, bacterial DNA, short base pairs and longer base pairs), determines the shape and measurement of the peak oxidative current of adenine and guanine, which is a molecular fingerprint for analyte detection. Due to the nature of DNA, we are able to amplify and manipulate it using biochemical methods. However, nucleic acid base pairing has to be taken into account and a strategy to detect target sequences with an electrode must be implemented. Based on the analyzed data from this experiment, this analytical method and measurement can be useful in detecting different physical and structural DNA damage and opens a way for studies on a potentially new diagnostic and treatment mechanisms. This work could potentially develop an entire new class of biosensors for DNA, RNA, and other nucleic acids, which would have lasting impacts in the field of sensor diagnostics.

OligoMinerApp: a web-server application for the design of genome-scale oligonucleotide in situ hybridization probes through the flexible OligoMiner environment.

Fluorescence in situ hybridization (FISH) is a powerful single-cell technique that harnesses nucleic acid base pairing to detect the abundance and positioning of cellular RNA and DNA molecules in fixed samples. Recent technology development has paved the way to the construction of FISH probes entirely from synthetic oligonucleotides (oligos), allowing the optimization of thermodynamic properties together with the opportunity to design probes against any sequenced genome. However, comparatively little progress has been made in the development of computational tools to facilitate the oligos design, and even less has been done to extend their accessibility. OligoMiner is an open-source and modular pipeline written in Python that introduces a novel method of assessing probe specificity that employs supervised machine learning to predict probe binding specificity from genome-scale sequence alignment information. However, its use is restricted to only those people who are confident with command line interfaces because it lacks a Graphical User Interface (GUI), potentially cutting out many researchers from this technology. Here, we present OligoMinerApp (http://oligominerapp.org), a web-based application that aims to extend the OligoMiner framework through the implementation of a smart and easy-to-use GUI and the introduction of new functionalities specially designed to make effective probe mining available to everyone.

Probing the Intercalation of Noscapine from Sodium Dodecyl Sulfate Micelles to Calf Thymus Deoxyribose Nucleic Acid: A Mechanistic Approach.

Noscapine (NOS) is efficient in inhibiting cellular proliferation and induces apoptosis in nonsmall cell, lung, breast, lymphatic, and prostate cancers. The micelle-assisted drug delivery is a well-known phenomenon; however, the proper mechanism is still unclear. Therefore, in the present study, we have shown a mechanistic approach for the delivery of NOS from sodium dodecyl sulfate (SDS) micelles to calf thymus deoxyribose nucleic acid (ctDNA) base-pairs using various spectroscopic techniques. The absorption and emission spectroscopy results revealed that NOS interacts with the SDS micelle and resides in its hydrophobic core. Further, the intercalation of NOS from SDS micelles to ctDNA was also shown by these techniques. The anisotropy and quenching results further confirmed the relocation of NOS from SDS micelles to ctDNA. The CD analysis suggested that SDS micelles do not perturb the structure of ctDNA, which supported that SDS micelles can be used as a safe delivery vehicle for NOS. This work may be helpful for the invention of advanced micelle-based vehicles for the delivery of an anticancer drug to their specific target site.

Local DNA Base Conformations and Ligand Intercalation in DNA Constructs Containing Optical Probes

Understanding local conformations of DNA at the level of individual nucleic acid bases and base pairs is important for elucidating molecular processes that depend on DNA sequence. Here, we apply linear absorption and circular dichroism measurements to the study of local DNA conformations, using the guanine base analog 6-methyl isoxanthopterin (6-MI) as a structural probe. We show that the spectroscopic properties of this probe can provide detailed information about the average local base and basepair conformations as a function of the surrounding DNA sequence. Based on these results we apply a simple theoretical model to calculate the circular dichroism spectra of 6-MI-substituted DNA constructs and show that our model can be used to extract information about how the local conformations of the 6-MI probe are influenced by the local base or basepair environment. We also use this probe to examine the pathway for the insertion (intercalation) of a tethered acridine ligand (9-amino-6-chloro methoxyacridine) into duplex DNA. We show that this model intercalator interacts with duplex DNA by a “displacement insertion intercalation” mechanism, whereby the acridine moiety is inserted into the DNA structure and displaces the base located opposite its attachment site. These findings suggest that site-specifically positioned base analog probes can be used to characterize the molecular and structural details of binding ligand effects on local base stacking and unstacking reactions in single- and double-stranded DNA and thus may help to define the molecular mechanisms of DNA-protein interactions that involve the site-specific intercalation of aromatic amino acid side chains into genomic DNA.

PH-Control in Aptamer-Based Diagnostics, Therapeutics, and Analytical Applications.

Aptamer binding has been used effectively for diagnostics, in-vivo targeting of therapeutics, and the construction and control of nanomachines. Nanostructures that respond to pH by releasing or changing affinity to a target have also been used for in vivo delivery, and in the construction of sensors and re-usable nanomachines. There are many applications that use aptamers together with pH-responsive materials, notably the targeted delivery of chemotherapeutics. However, the number of reported applications that directly use pH to control aptamer binding is small. In this review, we first discuss the use of aptamers with pH-responsive nanostructures for chemotherapeutic and other applications. We then discuss applications that use pH to denature or otherwise disrupt the binding of aptamers. Finally, we discuss motifs using non-canonical nucleic acid base pairing that can shift conformation in response to pH, followed by an overview of engineered pH-controlled aptamers designed using those motifs.

Biological and nanotechnological applications using interactions between ionic liquids and nucleic acids.

Nucleic acids have emerged as powerful biological and nanotechnological tools. In biological and nanotechnological experiments, methods of extracting and purifying nucleic acids from various types of cells and their storage are critical for obtaining reproducible experimental results. In nanotechnological experiments, methods for regulating the conformational polymorphism of nucleic acids and increasing sequence selectivity for base pairing of nucleic acids are important for developing nucleic acid-based nanomaterials. However, dearth of media that foster favourable behaviour of nucleic acids has been a bottleneck for promoting the biology and nanotechnology using the nucleic acids. Ionic liquids (ILs) are solvents that may be potentially used for controlling the properties of the nucleic acids. Here, we review researches regarding the behaviour of nucleic acids in ILs. The efficiency of extraction and purification of nucleic acids from biological samples is increased by IL addition. Moreover, nucleic acids in ILs show long-term stability, which maintains their structures and enhances nuclease resistance. Nucleic acids in ILs can be used directly in polymerase chain reaction and gene expression analysis with high efficiency. Moreover, the stabilities of the nucleic acids for duplex, triplex, and quadruplex (G-quadruplex and i-motif) structures change drastically with IL cation-nucleic acid interactions. Highly sensitive DNA sensors have been developed based on the unique changes in the stability of nucleic acids in ILs. The behaviours of nucleic acids in ILs detailed here should be useful in the design of nucleic acids to use as biological and nanotechnological tools.

Protein-ligand interfaces are polarized: discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes.

Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity. The resulting clear and significant chemical group matching preferences elucidate the code for protein-native ligand binding, similar to the dominant patterns found in nucleic acid base-pairing. On average, 90% of the keto and carboxylate oxygens occurring in the biological ligands formed direct H-bonds to the protein. A two-fold preference was found for protein atoms to act as H-bond donors and ligand atoms to act as acceptors, and 76% of all intermolecular H-bonds involved an amine donor. Together, the tight chemical and geometric constraints associated with satisfying donor groups generate a hydrogen-bonding lock that can be matched only by ligands bearing the right acceptor-rich key. Measuring an index of H-bond preference based on the observed chemical trends proved sufficient to predict other protein-ligand complexes and can be used to guide molecular design. The resulting Hbind and Protein Recognition Index software packages are being made available for rigorously defining intermolecular H-bonds and measuring the extent to which H-bonding patterns in a given complex match the preference key.

MUC1 aptamer-targeted DNA micelles for dual tumor therapy using doxorubicin and KLA peptide

Targeted delivery of DNA nanoparticles is a promising approach in cancer therapy. Using aptamers, target specific delivery of DNA nanoparticles can be achieved. Further, aptamers can indirectly improve drug encapsulation efficiency of DNA nanoparticles for drugs intercalated within nucleic acid base pairs. Using DNA blocks, a micellar hybrid nanoparticle was prepared for the targeted co-delivery of doxorubicin and a pro-apoptotic peptide, KLA to tumor cells. Results demonstrated that anti-MUC1 aptamer could specifically deliver the synthesized DNA micelle into MCF-7 cells by improving its cellular uptake. Additionally, co-delivery of doxorubicin and KLA could significantly enhance the therapeutic efficacy of the construct resulting in reduction of required dose of doxorubicin that is a pivotal point in reducing chemotherapeutics side effects. Moreover, DOX–KLA–anti-MUC1–micelle remarkably inhibited tumor growth of tumor-bearing mice when compared with free drug. DOX–KLA–anti-MUC1–micelle also reduced toxic effect of free doxorubicin as determined by percent of body weight loss and survival rate in vivo.