Publications by authors named "Chad A Mirkin"

594 Publications

Low-Density 2D Superlattices Assembled via Directional DNA Bonding.

Angew Chem Int Ed Engl 2021 Jul 26. Epub 2021 Jul 26.

Department of Materials Science and Engineering, Northwestern University, 2220 Campus Drive, Evanston, IL, 60208, USA.

It is critical to assemble nanoparticles (NPs) into superlattices with controlled symmetries and spacings on substrates for metamaterials applications, where such structural parameters dictate their properties. Here, we use DNA to assemble anisotropic NPs of three shapes-cubes, octahedra, and rhombic dodecahedra-on substrates and investigate their thermally induced reorganization into two-dimensional (2D) crystalline films. We report two new low-density 2D structures, including a honeycomb lattice based on octahedral NPs. The low-density lattices favored here are not usually seen when particles are crystallized via other bottom-up assembly techniques. Furthermore, we show that, consistent with the complementary contact model, a primary driving force for crystallization is the formation of directional, face-to-face DNA bonds between neighboring NPs and between NPs and the substrate. Our results can be used to deliberately prepare crystalline NP films with novel morphologies.
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http://dx.doi.org/10.1002/anie.202105796DOI Listing
July 2021

Lipid Nanoparticle Spherical Nucleic Acids for Intracellular DNA and RNA Delivery.

Nano Lett 2021 Jul 21. Epub 2021 Jul 21.

Lipid nanoparticle SNAs (LNP-SNAs) have been synthesized for the delivery of DNA and RNA to targets in the cytoplasm of cells. Both the composition of the LNP core and surface-presented DNA sequences contribute to LNP-SNA activity. G-rich sequences enhance the activity of LNP-SNAs compared to T-rich sequences. In the LNP core, increased cholesterol content leads to greater activity. Optimized LNP-SNA candidates reduce the siRNA concentration required to silence mRNA by 2 orders of magnitude compared to liposome-based SNAs. In addition, the LNP-SNA architectures alter biodistribution and efficacy profiles in mice. For example, mRNA within LNP-SNAs injected intravenously is primarily expressed in the spleen, while mRNA encapsulated by LNPs (no DNA on the surface) was expressed primarily in the liver with a relatively small amount in the spleen. These data show that the activity and biodistribution of LNP-SNA architectures are different from those of conventional liposomal SNAs and therefore potentially can be used to target tissues.
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http://dx.doi.org/10.1021/acs.nanolett.1c01973DOI Listing
July 2021

Synergistic Immunostimulation through the Dual Activation of Toll-like Receptor 3/9 with Spherical Nucleic Acids.

ACS Nano 2021 Jul 19. Epub 2021 Jul 19.

Toll-like receptors (TLRs) are a family of proteins that modulate the innate immune system and control the initiation of downstream immune responses. Spherical nucleic acids (SNAs) designed to stimulate single members of the TLR family (, TLR7 or TLR9) have shown utility in cancer immunotherapy. We hypothesized that SNAs synthesized with multiple TLR agonists would enable the simultaneous activation of multiple TLR pathways for maximally synergistic immune activation. Here, we describe the synthesis of SNAs that incorporate both a TLR3 agonist (polyinosinic:polycytidylic acid, poly(I:C)) and TLR9 agonist (CpG oligonucleotide) on the same liposomal scaffold. In this design, CpG comprises the SNA oligonucleotide shell, and poly(I:C) is encapsulated in the liposome core. These dual-TLR activating SNAs efficiently codeliver high quantities of both agonists to the same target cell, yielding enhanced immunostimulation in various murine and human antigen-presenting cells (APCs). Moreover, codelivery of TLR agonists using the SNA both synchronizes and prolongs the duration of costimulatory molecule and major histocompatibility complex class II expression in APCs, which has been shown to be important for efficient downstream immune responses. Taken together, this SNA design provides a strategy for potently activating immune cells and increasing the efficiency of their activation, which likely will inform the preparation of nanomaterials for highly potent immunotherapies.
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http://dx.doi.org/10.1021/acsnano.1c03093DOI Listing
July 2021

Crystal structure engineering in multimetallic high-index facet nanocatalysts.

Proc Natl Acad Sci U S A 2021 Jun;118(26)

Department of Chemistry, Northwestern University, Evanston, IL 60208;

In the context of metal particle catalysts, composition, shape, exposed facets, crystal structure, and atom distribution dictate activity. While techniques have been developed to control each of these parameters, there is no general method that allows one to optimize all parameters in the context of polyelemental systems. Herein, by combining a solid-state, Bi-influenced, high-index facet shape regulation strategy with thermal annealing, we achieve control over crystal structure and atom distribution on the exposed high-index facets, resulting in an unprecedentedly diverse library of chemically disordered and ordered multimetallic (Pt, Co, Ni, Cu, Fe, and Mn) tetrahexahedral (THH) nanoparticles. Density functional theory calculations show that surface Bi modification stabilizes the {210} high-index facets of the nanoparticles, regardless of their internal atomic ordering. Moreover, we find that the ordering transition temperatures for the nanoparticles are dependent on their composition, and, in the case of PtFe THH nanoparticles, increasing Ni substitution leads to an order-to-disorder transition at 900 °C. Finally, we have discovered that ordered intermetallic THH PtCo nanocatalysts exhibit a catalytic performance superior to disordered THH PtCo nanoparticles and commercial Pt/C catalysts toward methanol electrooxidation, highlighting the importance of crystal structure and atom distribution control on high-index facets in nanoscale catalysts.
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http://dx.doi.org/10.1073/pnas.2105722118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255997PMC
June 2021

Electrochemical Polymer Pen Lithography.

Small 2021 Jul 10;17(28):e2100662. Epub 2021 Jun 10.

Department of Chemistry, Northwestern University, 2145 Sheridan Rd., Evanston, IL, 60208, USA.

The development of a massively parallel lithographic technique called electrochemical polymer pen lithography is reported. Pyramidal pen arrays, consisting of more than 10 000 hydrogel pens loaded with metal salts, are integrated into a three-electrode cell and used to locally reduce ions at each pen tip. This system enables high-throughput patterning of a variety of metallic inks (e.g., Ni , Pt , Ag ) on the nanometer to micrometer length scale. By incorporating a z-direction piezo actuator, the extension length and dwell time can be used to precisely define feature dimensions (210 to 10 µm in width, and up to 900 nm in height, thus far). Furthermore, by controlling the potential and precursor concentrations, more than one element can be simultaneously deposited, creating a new tool for the synthesis of alloy features, such as NiCo, which are relevant for catalysis. Importantly, this methodology enables fine control over feature size and composition in a single pattern, which may make it ultimately useful for rapid, high-throughput combinatorial screening of metallic features.
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http://dx.doi.org/10.1002/smll.202100662DOI Listing
July 2021

Redefining Protein Interfaces within Protein Single Crystals with DNA.

J Am Chem Soc 2021 Jun 5;143(23):8925-8934. Epub 2021 Jun 5.

Department of Chemistry and International Institute for Nanotechnology, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States.

Proteins are exquisite nanoscale building blocks: molecularly pure, chemically addressable, and inherently selective for their evolved function. The organization of proteins into single crystals with high positional, orientational, and translational order results in materials where the location of every atom can be known. However, controlling the organization of proteins is challenging due to the myriad interactions that define protein interfaces within native single crystals. Recently, we discovered that introducing a single DNA-DNA interaction between protein surfaces leads to changes in the packing of proteins within single crystals and the protein-protein interactions (PPIs) that arise. However, modifying specific PPIs to effect deliberate changes to protein packing is an unmet challenge. In this work, we hypothesized that disrupting and replacing a highly conserved PPI with a DNA-DNA interaction would enable protein packing to be modulated by exploiting the programmability of the introduced oligonucleotides. Using concanavalin A (ConA) as a model protein, we circumvent potentially deleterious mutagenesis and exploit the selective binding of ConA toward mannose to noncovalently attach DNA to the protein surface. We show that DNA association eliminates the major PPI responsible for crystallization of native ConA, thereby allowing subtle changes to DNA design (length, complementarity, and attachment position) to program distinct changes to ConA packing, including the realization of three novel crystal structures and the deliberate expansion of ConA packing along a single crystallographic axis. These findings significantly enhance our understanding of how DNA can supersede native PPIs to program protein packing within ordered materials.
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http://dx.doi.org/10.1021/jacs.1c04191DOI Listing
June 2021

Impact of Liposomal Spherical Nucleic Acid Structure on Immunotherapeutic Function.

ACS Cent Sci 2021 May 15;7(5):892-899. Epub 2021 Apr 15.

Department of Chemistry, International Institute for Nanotechnology, Department of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208, United States.

Liposomal spherical nucleic acids (L-SNAs) show significant promise as cancer immunotherapeutics. L-SNAs are highly modular nanoscale assemblies defined by a dense, upright radial arrangement of oligonucleotides around a liposomal core. Herein, we establish a set of L-SNA design rules by studying the biological and immunological properties of L-SNAs as a function of liposome composition. To achieve this, we synthesized liposomes where the lipid phosphatidylcholine headgroup was held constant, while the diacyl lipid tail chain length and degree of saturation were varied, using either 1,2-dioleylphosphatidylcholine (DOPC), 1,2-dimyristoyl-phosphatidylcholine (DMPC), 1,2-dipalmitoylphosphatidylcholine (DPPC), or 1,2-distearoyl-phosphatidylcholine (DSPC). These studies show that the identity of the constituent lipid dictates the DNA loading, cellular uptake, serum stability, immunostimulatory activity, and lymph node accumulation of the L-SNA. Furthermore, in the 4T1 mouse model of triple-negative breast cancer (TNBC), the subcutaneous administration of immunostimulatory L-SNAs synthesized with DPPC significantly decreases the production of lung metastases and delays tumor growth as compared to L-SNAs synthesized using DOPC, due to the enhanced stability of L-SNAs synthesized with DPPC over those synthesized with DOPC. Moreover, the inclusion of cell lysates derived from Py8119 TNBC cells as antigen sources in L-SNAs leads to a significant increase in antitumor efficacy in the Py8119 model when lysates are encapsulated in the cores of L-SNAs synthesized with DPPC rather than DOPC, presumably due to increased codelivery of adjuvant and antigen to dendritic cells . This difference is further amplified when using lysates from oxidized Py8119 cells as a more potent antigen source, revealing synergy between the lysate preparation method and liposome composition in synthesizing immunotherapeutic L-SNAs. Together, this work shows that the biological properties and immunomodulatory activity of L-SNAs can be modulated by exchanging liposome components, providing another handle for the rational design of nanoscale immunotherapeutics.
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http://dx.doi.org/10.1021/acscentsci.1c00181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161491PMC
May 2021

Programming Fluorogenic DNA Probes for Rapid Detection of Steroids.

Angew Chem Int Ed Engl 2021 07 1;60(28):15260-15265. Epub 2021 Jun 1.

Department of Chemistry and International Institute for, Nanotechnology, Northwestern University, 2145 Sheridan Road, Evanston, IL, 60208, USA.

The ability of aptamers to recognize a variety of different molecules has fueled their emergence as recognition agents to probe complex media and cells. Many detection strategies require aptamer binding to its target to result in a dramatic change in structure, typically from an unfolded to a folded state. Here, we report a strategy based on forced intercalation (FIT) that increases the scope of aptamer recognition by transducing subtle changes in aptamer structures into fluorescent readouts. By screening a library of green-fluorescent FIT-aptamers whose design is guided by computational modeling, we could identify hits that sense steroids like dehydroepiandrosterone sulfate (DHEAS) down to 1.3 μM with no loss in binding affinity compared to the unmodified aptamer. This enabled us to study DHEAS in clinical serum samples with several advantages over gold standard methods, including rapid readout (<30 min), simple instrumentation (plate-reader), and low sample volumes (10 μL).
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http://dx.doi.org/10.1002/anie.202103440DOI Listing
July 2021

Multi-State Dynamic Coordination Complexes Interconverted through Counterion-Controlled Phase Transfer.

Inorg Chem 2021 Apr 10;60(7):4755-4763. Epub 2021 Mar 10.

Department of Chemistry and International Institute for Nanotechnology, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.

We studied a series of dynamic weak-link approach (WLA) complexes that can be shuttled between two immiscible solvents and switched between two structural states via ion exchange. Here, we established that hydrophobic anions transfer cationic, amphiphilic complexes from the aqueous phase to the organic phase, while a chloride source reverses the process. As a result of the dynamic metal coordination properties of WLA complexes, the denticity of these complexes (mono- to bi-) can be modulated as they partition into different phases. In addition, we discovered that heteroligated complexes bearing ligands of different donor strengths preferentially rearrange into two homoligated complexes that are phase-partitioned to maximize the number of stronger coordination bonds. This behavior is not observed in systems with one solvent, highlighting the dynamic and stimuli-responsive nature of hemilabile ligands in a multiphasic solvent environment. Taken together, this work shows that the highly reconfigurable WLA modality can enable the design of biphasic reaction networks or chemical separations driven by straightforward salt metathesis reactions.
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http://dx.doi.org/10.1021/acs.inorgchem.0c03708DOI Listing
April 2021

Attenuation of Abnormal Scarring Using Spherical Nucleic Acids Targeting Transforming Growth Factor Beta 1.

ACS Appl Bio Mater 2020 Dec 13;3(12):8603-8610. Epub 2020 Nov 13.

Department of Chemical and Biological Engineering, International Institute for Nanotechnology, Department of Materials Science and Engineering, and Department of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208, United States.

Abnormal scarring is a consequence of dysregulation in the wound healing process, with limited options for effective and noninvasive therapies. Given the ability of spherical nucleic acids (SNAs) to penetrate skin and regulate gene expression within, we investigated whether gold-core SNAs (AuSNAs) and liposome-core SNAs (LSNAs) bearing antisense oligonucleotides targeting transforming growth factor beta 1 (TGF-1) can function as a topical therapy for scarring. Importantly, both SNA constructs appreciably downregulated TGF-1 protein expression in primary hypertrophic and keloid scar fibroblasts in vitro. In vivo, topically applied AuSNAs and LSNAs downregulated TGF-1 protein expression levels and improved scar histology as determined by the scar elevation index. These data underscore the potential of SNAs as a localized, self-manageable treatment for skin-related diseases and disorders that are driven by increased gene expression.
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http://dx.doi.org/10.1021/acsabm.0c00990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946158PMC
December 2020

DNA-Directed Protein Packing within Single Crystals.

Chem 2020 Apr 23;6(4):1007-1017. Epub 2020 Mar 23.

Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA.

Designed DNA-DNA interactions are investigated for their ability to modulate protein packing within single crystals of mutant green fluorescent proteins (mGFPs) functionalized with a single DNA strand (mGFP-DNA). We probe the effects of DNA sequence, length, and protein-attachment position on the formation and protein packing of mGFP-DNA crystals. Notably, when complementary mGFP-DNA conjugates are introduced to one another, crystals form with nearly identical packing parameters, regardless of sequence if the number of bases is equivalent. DNA complementarity is essential, because experiments with non-complementary sequences produce crystals with different protein arrangements. Importantly, the DNA length and its position of attachment on the protein markedly influence the formation of and protein packing within single crystals. This work shows how designed DNA interactions can be used to influence the growth and packing in X-ray diffraction quality protein single crystals and is thus an important step forward in protein crystal engineering.
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http://dx.doi.org/10.1016/j.chempr.2020.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946157PMC
April 2020

Twin Pathways: Discerning the Origins of Multiply Twinned Colloidal Nanoparticles.

Angew Chem Int Ed Engl 2021 03 9;60(13):6858-6863. Epub 2021 Feb 9.

International Institute for Nanotechnology, Northwestern University, Evanston, IL, 60208, USA.

The structure of multiply twinned particles (MTPs) provides an example of how specific crystallographic features dictate the geometric shape of finite-sized crystals. The formation of MTPs during colloidal synthesis can occur through at least two different pathways: 1) growth from multiply twinned seeds or 2) the stepwise formation of new twin boundaries on single-crystalline seeds (either by particle overgrowth or multiparticle attachment). By utilizing in situ transmission electron microscopy, recent studies have provided real-time evidence for both pathways. Looking forward, the knowledge of specific evolution pathways that occur under a given synthetic condition will aid in the design of robust MTP syntheses. More importantly, further studies pertaining to the structural evolution and energetics of nanoparticles are needed to provide a complete understanding of MTP formation pathways.
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http://dx.doi.org/10.1002/anie.202015166DOI Listing
March 2021

Corner-, edge-, and facet-controlled growth of nanocrystals.

Sci Adv 2021 Jan 15;7(3). Epub 2021 Jan 15.

Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.

The ability to precisely control nanocrystal (NC) shape and composition is useful in many fields, including catalysis and plasmonics. Seed-mediated strategies have proven effective for preparing a wide variety of structures, but a poor understanding of how to selectively grow corners, edges, and facets has limited the development of a general strategy to control structure evolution. Here, we report a universal synthetic strategy for directing the site-specific growth of anisotropic seeds to prepare a library of designer nanostructures. This strategy leverages nucleation energy barrier profiles and the chemical potential of the growth solution to control the site-specific growth of NCs into exotic shapes and compositions. This strategy can be used to not only control where growth occurs on anisotropic seeds but also control the exposed facets of the newly grown regions. NCs of many shapes are synthesized, including over 10 here-to-fore never reported NCs and, in principle, many others are possible.
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http://dx.doi.org/10.1126/sciadv.abf1410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810373PMC
January 2021

Electron-Equivalent Valency through Molecularly Well-Defined Multivalent DNA.

J Am Chem Soc 2021 02 22;143(4):1752-1757. Epub 2021 Jan 22.

Department of Chemistry and International Institute for Nanotechnology, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.

Oligonucleotide-functionalized nanoparticles (NPs), also known as "programmable atom equivalents" (PAEs), have emerged as a class of versatile building blocks for generating colloidal crystals with tailorable structures and properties. Recent studies have shown that, at small size and low DNA grafting density, PAEs can also behave as "electron equivalents" (EEs), roaming through and stabilizing a complementary PAE sublattice. However, it has been challenging to obtain a detailed understanding of EE-PAE interactions and the underlying colloidal metallicity because there is inherent polydispersity in the number of DNA strands on the surfaces of these NPs; thus, the structural uniformity and tailorability of NP-based EEs are somewhat limited. Herein, we report a strategy for synthesizing colloidal crystals where the EEs are templated by small molecules, instead of NPs, and functionalized with a precise number of DNA strands. When these molecularly precise EEs are assembled with complementary NP-based PAEs, X-ray scattering and electron microscopy reveal the formation of three distinct "metallic" phases. Importantly, we show that the thermal stability of these crystals is dependent on the number of sticky ends per EE, while lattice symmetry is controlled by the number and orientation of EE sticky ends on the PAEs. Taken together, this work introduces the notion that, unlike conventional electrons, EEs that are molecular in origin can have a defined valency that can be used to influence and guide specific phase formation.
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http://dx.doi.org/10.1021/jacs.0c11843DOI Listing
February 2021

Probing the Consequences of Cubic Particle Shape and Applied Field on Colloidal Crystal Engineering with DNA.

Angew Chem Int Ed Engl 2021 02 22;60(8):4065-4069. Epub 2020 Dec 22.

Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL, 60208, USA.

In a magnetic field, cubic Fe O nanoparticles exhibit assembly behavior that is a consequence of a competition between magnetic dipole-dipole and ligand interactions. In most cases, the interactions between short hydrophobic ligands dominate and dictate assembly outcome. To better tune the face-to-face interactions, cubic Fe O nanoparticles were functionalized with DNA. Their assembly behaviors were investigated both with and without an applied magnetic field. Upon application of a field, the tilted orientation of cubes, enabled by the flexible DNA ligand shell, led to an unexpected crystallographic alignment of the entire superlattice, as opposed to just the individual particles, along the field direction as revealed by small and wide-angle X-ray scattering. This observation is dependent upon DNA length and sequence and cube dimensions. Taken together, these studies show how combining physical and chemical control can expand the possibilities of crystal engineering with DNA.
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http://dx.doi.org/10.1002/anie.202012907DOI Listing
February 2021

Position- and Orientation-Controlled Growth of Wulff-Shaped Colloidal Crystals Engineered with DNA.

Adv Mater 2020 Nov 21;32(47):e2005316. Epub 2020 Oct 21.

International Institute for Nanotechnology, Northwestern University, Evanston, IL, 60208, USA.

Colloidal crystals have emerged as promising candidates for building optical microdevices. Techniques now exist for synthesizing them with control over their nanoscale features (e.g., particle compositions, sizes, shapes, and lattice parameters and symmetry); however, the ability to tune macroscale structural features, such as the relative positions of crystals to one another and lattice orientations, has yet to be realized. Here, inspiration is drawn from epitaxial growth strategies in atomic crystallization, and patterned substrates are prepared that, when used in conjunction with DNA-mediated nanoparticle crystallization, allow for control over individual Wulff-shaped crystal growth, location, and orientation. In addition, the approach allows exquisite control over the patterned substrate/crystal lattice mismatch, something not yet realized for any epitaxy process. This level of structural control is a significant step toward realizing complex, integrated devices with colloidal crystal components, and this approach provides a model system for further exploration in epitaxy systems.
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http://dx.doi.org/10.1002/adma.202005316DOI Listing
November 2020

Synthesis of Metal-Capped Semiconductor Nanowires from Heterodimer Nanoparticle Catalysts.

J Am Chem Soc 2020 Oct 20;142(43):18324-18329. Epub 2020 Oct 20.

Semiconductor nanowires (NWs) capped with metal nanoparticles (NPs) show multifunctional and synergistic properties, which are important for applications in the fields of catalysis, photonics, and electronics. Conventional colloidal syntheses of this class of hybrid structures require complex sequential seeded growth, where each section requires its own set of growth conditions, and methods for preparing such wires are not universal. Here, we report a new and general method for synthesizing metal-semiconductor nanohybrids based on particle catalysts, prepared by scanning probe block copolymer lithography, and chemical vapor deposition. In this process, metallic heterodimer NPs were used as catalysts for NW growth to form semiconductor NWs capped with metallic particles (Au, Ag, Co, Ni). Interestingly, the growth processes for NWs on NPs are regioselective and controlled by the chemical composition of the metallic heterodimer used. Using a systematic experimental approach, paired with density functional theory calculations, we were able to postulate three different growth modes, one without precedent.
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http://dx.doi.org/10.1021/jacs.0c09222DOI Listing
October 2020

Mie-Resonant Three-Dimensional Metacrystals.

Nano Lett 2020 11 15;20(11):8096-8101. Epub 2020 Oct 15.

Department of Physics, Chungbuk National University, Cheongju 28644, Republic of Korea.

Optical metamaterials, engineered to exhibit electromagnetic properties not found in natural materials, may enable new light-based applications including cloaking and optical computing. While there have been significant advances in the fabrication of two-dimensional metasurfaces, planar structures create nontrivial angular and polarization sensitivities, making omnidirectional operation impossible. Although three-dimensional (3D) metamaterials have been proposed, their fabrication remains challenging. Here, we use colloidal crystal engineering with DNA to prepare isotropic 3D metacrystals from Au nanocubes. We show that such structures can exhibit refractive indices as large as ∼8 in the mid-infrared, far greater than that of common high-index dielectrics. Additionally, we report the first observation of multipolar Mie resonances in metacrystals with well-formed habits, occurring in the mid-infrared for submicrometer metacrystals, which we measured using synchrotron infrared microspectroscopy. Finally, we predict that arrays of metacrystals could exhibit negative refraction. The results present a promising platform for engineering devices with unnatural optical properties.
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http://dx.doi.org/10.1021/acs.nanolett.0c03089DOI Listing
November 2020

Halide perovskite nanocrystal arrays: Multiplexed synthesis and size-dependent emission.

Sci Adv 2020 Sep 23;6(39). Epub 2020 Sep 23.

Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, USA.

Halide perovskites have exceptional optoelectronic properties, but a poor understanding of the relationship between crystal dimensions, composition, and properties limits their use in integrated devices. We report a new multiplexed cantilever-free scanning probe method for synthesizing compositionally diverse and size-controlled halide perovskite nanocrystals spanning square centimeter areas. Single-particle photoluminescence studies reveal multiple independent emission modes due to defect-defined band edges with relative intensities that depend on crystal size at a fixed composition. Smaller particles, but ones with dimensions that exceed the quantum confinement regime, exhibit blue-shifted emission due to reabsorption of higher-energy modes. Six different halide perovskites have been synthesized, including a layered Ruddlesden-Popper phase, and the method has been used to prepare functional solar cells based on single nanocrystals. The ability to pattern arrays of multicolor light-emitting nanocrystals opens avenues toward the development of optoelectronic devices, including optical displays.
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http://dx.doi.org/10.1126/sciadv.abc4959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531881PMC
September 2020

Device-quality, reconfigurable metamaterials from shape-directed nanocrystal assembly.

Proc Natl Acad Sci U S A 2020 09 17;117(35):21052-21057. Epub 2020 Aug 17.

International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208;

Anchoring nanoscale building blocks, regardless of their shape, into specific arrangements on surfaces presents a significant challenge for the fabrication of next-generation chip-based nanophotonic devices. Current methods to prepare nanocrystal arrays lack the precision, generalizability, and postsynthetic robustness required for the fabrication of device-quality, nanocrystal-based metamaterials [Q. Y. Lin et al. Nano Lett. 15, 4699-4703 (2015); V. Flauraud et al., Nat. Nanotechnol. 12, 73-80 (2017)]. To address this challenge, we have developed a synthetic strategy to precisely arrange any anisotropic colloidal nanoparticle onto a substrate using a shallow-template-assisted, DNA-mediated assembly approach. We show that anisotropic nanoparticles of virtually any shape can be anchored onto surfaces in any desired arrangement, with precise positional and orientational control. Importantly, the technique allows nanoparticles to be patterned over a large surface area, with interparticle distances as small as 4 nm, providing the opportunity to exploit light-matter interactions in an unprecedented manner. As a proof-of-concept, we have synthesized a nanocrystal-based, dynamically tunable metasurface (an anomalous reflector), demonstrating the potential of this nanoparticle-based metamaterial synthesis platform.
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http://dx.doi.org/10.1073/pnas.2006797117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474604PMC
September 2020

Endosomal Organization of CpG Constructs Correlates with Enhanced Immune Activation.

Nano Lett 2020 08 31;20(8):6170-6175. Epub 2020 Jul 31.

This Letter describes how the endosomal organization of immunostimulatory nanoconstructs can tune the activation of macrophages. Nanoconstructs composed of gold nanoparticles conjugated with unmethylated cytosine-phosphate-guanine (CpG) oligonucleotides have distinct endosomal distributions depending on the surface curvature. Mixed-curvature constructs produce a relatively high percentage of hollow endosomes, where constructs accumulated primarily along the interior edges. These constructs achieved a higher level of toll-like receptor (TLR) 9 activation along with the enhanced secretion of proinflammatory cytokines and chemokines compared to constant-curvature constructs that aggregated mostly in the center of the endosomes. Our results underscore the importance of intraendosomal interactions in regulating immune responses and targeted delivery.
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http://dx.doi.org/10.1021/acs.nanolett.0c02536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609249PMC
August 2020

Protein Spherical Nucleic Acids for Live-Cell Chemical Analysis.

J Am Chem Soc 2020 08 24;142(31):13350-13355. Epub 2020 Jul 24.

We report the development of a new strategy for the chemical analysis of live cells based on protein spherical nucleic acids (ProSNAs). The ProSNA architecture enables analyte detection via the highly programmable nucleic acid shell or a functional protein core. As a proof-of-concept, we use an i-motif as the nucleic acid recognition element to probe pH in living cells. By interfacing the i-motif with a forced-intercalation readout, we introduce a quencher-free approach that is resistant to false-positive signals, overcoming limitations associated with conventional fluorophore/quencher-based gold NanoFlares. Using glucose oxidase as a functional protein core, we show activity-based, amplified sensing of glucose. This enzymatic system affords greater than 100-fold fluorescence turn on in buffer, is selective for glucose in the presence of close analogs (i.e., glucose-6-phosphate), and can detect glucose above a threshold concentration of ∼5 μM, which enables the study of relative changes in intracellular glucose concentrations.
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http://dx.doi.org/10.1021/jacs.0c06866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473486PMC
August 2020

Tumor cell lysate-loaded immunostimulatory spherical nucleic acids as therapeutics for triple-negative breast cancer.

Proc Natl Acad Sci U S A 2020 07 15;117(30):17543-17550. Epub 2020 Jul 15.

Department of Chemistry, Northwestern University, Evanston, IL 60208;

Highly heterogenous cancers, such as triple-negative breast cancer (TNBC), remain challenging immunotherapeutic targets. Herein, we describe the synthesis and evaluation of immunotherapeutic liposomal spherical nucleic acids (SNAs) for TNBC therapy. The SNAs comprise immunostimulatory oligonucleotides (CpG-1826) as adjuvants and encapsulate lysates derived from TNBC cell lines as antigens. The resulting nanostructures (Lys-SNAs) enhance the codelivery of adjuvant and antigen to immune cells when compared to simple mixtures of lysates with linear oligonucleotides both in vitro and in vivo, and reduce tumor growth relative to simple mixtures of lysate and CpG-1826 (Lys-Mix) in both Py230 and Py8119 orthotopic syngeneic mouse models of TNBC. Furthermore, oxidizing TNBC cells prior to lysis and incorporation into SNAs (OxLys-SNAs) significantly increases the activation of dendritic cells relative to their nonoxidized counterparts. When administered peritumorally in vivo in the EMT6 mouse mammary carcinoma model, OxLys-SNAs significantly increase the population of cytotoxic CD8+ T cells and simultaneously decrease the population of myeloid derived suppressor cells (MDSCs) within the tumor microenvironment, when compared with Lys-SNAs and simple mixtures of oxidized lysates with CpG-1826. Importantly, animals administered OxLys-SNAs exhibit significant antitumor activity and prolonged survival relative to all other treatment groups, and resist tumor rechallenge. Together, these results show that the way lysates are processed and packaged has a profound impact on their immunogenicity and therapeutic efficacy. Moreover, this work points toward the potential of oxidized tumor cell lysate-loaded SNAs as a potent class of immunotherapeutics for cancers lacking common therapeutic targets.
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http://dx.doi.org/10.1073/pnas.2005794117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395518PMC
July 2020

DNA-Based Nanostructures for Live-Cell Analysis.

J Am Chem Soc 2020 07 23;142(26):11343-11356. Epub 2020 Jun 23.

DNA-based probes constitute a versatile platform for making biological measurements due to their ability to recognize both nucleic acid and non-nucleic acid targets, ease of synthesis and chemical modification, amenability to be interfaced with signal amplification schemes, and inherent biocompatibility. Here, we provide a historical perspective of how a transition from linear DNA structures toward more structurally complex nanostructures has revolutionized live-cell analysis. Modulating the structure gives rise to probes that can enter cells without the aid of transfection reagents and can detect, track, and quantify analytes in live cells at the single-organelle, single-cell, tissue section, and whole organism levels. We delineate the advantages and disadvantages associated with different probe architectures and describe the advances enabled by these structures for elucidating fundamental biology as well as developing improved diagnostic and theranostic systems. We also discuss the outstanding challenges in the field and outline potential solutions.
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http://dx.doi.org/10.1021/jacs.0c04978DOI Listing
July 2020

High-Index-Facet Metal-Alloy Nanoparticles as Fuel Cell Electrocatalysts.

Adv Mater 2020 Jul 22;32(30):e2002849. Epub 2020 Jun 22.

Department of Materials Science and Engineering, Northwestern University, 2220 Campus Drive, Evanston, IL, 60208, USA.

A method to introduce high-index facets into colloidally synthesized nanoparticles is used to produce compositionally uniform Pt-M (M = Ni, Co, and Cu) and Rh-M (M = Ni and Co) tetrahexahedral nanoparticles. The realization of this method allows for a systematic study of catalyst activity as a function of particle composition for various electrooxidation reactions of liquid fuels (formic acid, methanol, and ethanol). The individual contributions of their high-index facets, internal alloying of transition metals, and surface Bi modification to their electrocatalytic properties are experimentally explored, resulting in three key findings. First, the presence of high-index facets is favorable for improving the catalytic activity for all three classes of reactions studied. Second, the effect of transition metal alloying on catalytic activity differs from reaction to reaction. For methanol electrooxidation in an acid electrolyte, due to the contribution from surface Bi modification being negligible, transition metal alloying can significantly the improve overall catalytic efficiency. However, for the other studied reactions, where the surface Bi is highly favorable for improving catalytic activity, there is little influence from transition metal alloying. Finally, multimetallic tetrahexahedral particles have improved stabilities during prolonged operation compared to their monometallic counterparts due to the presence of the alloyed transition metal atoms.
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http://dx.doi.org/10.1002/adma.202002849DOI Listing
July 2020

Automated Synthesis and Purification of Guanidine-Backbone Oligonucleotides.

Curr Protoc Nucleic Acid Chem 2020 06;81(1):e110

Department of Chemistry and the International Institute for Nanotechnology, Northwestern University, Evanston, Illinois.

This protocol describes a method based on iodine and a base as mild coupling reagents to synthetize deoxyribonucleic guanidines (DNGs)-oligodeoxynucleotide analogues with a guanidine backbone. DNGs display unique properties, such as high cellular uptake with low toxicity and increased stability against nuclease degradation, but have been impeded in their development by the requirement for toxic and iterative manual synthesis protocols. The novel synthesis method reported here eliminates the need for the toxic mercuric chloride and pungent thiophenol that were critical to previous DNG synthesis methods and translates their synthesis to a MerMade 12 automated oligonucleotide synthesizer. This method can be used to synthesize DNG strands up to 20 bases in length, along with 5'-DNG-DNA-3' chimeras, at 1- to 5-μmol scales in a fully automated manner. We also present detailed and accessible instructions to adapt the MerMade 12 oligonucleotide synthesizer to enable the parallel synthesis of DNG and DNA/RNA oligonucleotides. Because DNG linkages alter the overall charge of the oligonucleotides, we also describe purification strategies to generate oligonucleotides with varying lengths and numbers of DNGs, based on extraction or preparative-scale gel electrophoresis, along with methods to characterize the final products. Overall, this article provides an overview of the synthesis, purification, and handling of DNGs and mixed-charge DNG-DNA oligonucleotides. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Preparation of a MerMade synthesizer for guanidine couplings Basic Protocol 2: Synthesis of DNG strands on a MerMade synthesizer Basic Protocol 3: Purification of DNG strands using preparative acetic acid urea (AU) PAGE Basic Protocol 4: Characterization of DNG strands using MALDI-TOF MS Basic Protocol 5: Characterization of DNG strands using AU PAGE Support Protocol 1: Synthesis of initiator-functionalized CPG Support Protocol 2: Synthesis of thiourea monomer.
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http://dx.doi.org/10.1002/cpnc.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373344PMC
June 2020

Defining the Design Parameters for Enzyme Delivery Through Protein Spherical Nucleic Acids.

ACS Cent Sci 2020 May 27;6(5):815-822. Epub 2020 Apr 27.

Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States.

The translation of proteins as effective intracellular drug candidates is limited by the challenge of cellular entry and their vulnerability to degradation. To advance their therapeutic potential, cell-impermeable proteins can be readily transformed into protein spherical nucleic acids (ProSNAs) by densely functionalizing their surfaces with DNA, yielding structures that are efficiently taken up by cells. Because small structural changes in the chemical makeup of a conjugated ligand can affect the bioactivity of the associated protein, structure-activity relationships of the linker bridging the DNA and the protein surface and the DNA sequence itself are investigated on the ProSNA system. In terms of attachment chemistry, DNA-based linkers promote a sevenfold increase in cellular uptake while maintaining enzymatic activity as opposed to hexaethylene glycol (HEG, Spacer18) linkers. Additionally, the employment of G-quadruplex-forming sequences increases cellular uptake up to fourfold. When translating to murine models, the ProSNA with a DNA-only shell exhibits increased blood circulation times and higher accumulation in major organs, including lung, kidney, and spleen, regardless of sequence. Importantly, ProSNAs with an all-oligonucleotide shell retain their enzymatic activity in tissue, whereas the native protein loses all function. Taken together, these results highlight the value of structural design in guiding ProSNA biological fate and activity and represent a significant step forward in the development of intracellular protein-based therapeutics.
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http://dx.doi.org/10.1021/acscentsci.0c00313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256953PMC
May 2020

Dual-Readout Sandwich Immunoassay for Device-Free and Highly Sensitive Anthrax Biomarker Detection.

Anal Chem 2020 06 21;92(11):7845-7851. Epub 2020 May 21.

International Institute for Nanotechnology, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60608, United States.

We report a dual-readout, AuNP-based sandwich immunoassay for the device-free colorimetric and sensitive scanometric detection of disease biomarkers. An AuNP-antibody conjugate serves as a signal transduction and amplification agent by promoting the reduction and deposition of either platinum or gold onto its surface, generating corresponding colorimetric or light scattering (scanometric) signals, respectively. We apply the Pt-based colorimetric readout of this assay to the discovery of a novel monoclonal antibody (mAb) sandwich pair for the detection of an anthrax protective antigen (PA). The identified antibody pair detects PA down to 1 nM in phosphate-buffered saline and 5 nM in human serum, which are physiologically relevant concentrations. Reducing gold rather than platinum onto the mAb-AuNP sandwich enables scanometric detection of subpicomolar PA concentrations, over 3 orders of magnitude more sensitive than the colorimetric readout.
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http://dx.doi.org/10.1021/acs.analchem.0c01090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418077PMC
June 2020

Colloidal crystal engineering with metal-organic framework nanoparticles and DNA.

Nat Commun 2020 05 19;11(1):2495. Epub 2020 May 19.

Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL, 60208, USA.

Colloidal crystal engineering with nucleic acid-modified nanoparticles is a powerful way for preparing 3D superlattices, which may be useful in many areas, including catalysis, sensing, and photonics. To date, the building blocks studied have been primarily based upon metals, metal oxides, chalcogenide semiconductors, and proteins. Here, we show that metal-organic framework nanoparticles (MOF NPs) densely functionalized with oligonucleotides can be programmed to crystallize into a diverse set of superlattices with well-defined crystal symmetries and compositions. Electron microscopy and small-angle X-ray scattering characterization confirm the formation of single-component MOF superlattices, binary MOF-Au single crystals, and two-dimensional MOF nanorod assemblies. Importantly, DNA-modified porphyrinic MOF nanorods (PCN-222) were assembled into 2D superlattices and found to be catalytically active for the photooxidation of 2-chloroethyl ethyl sulfide (CEES, a chemical warfare simulant of mustard gas). Taken together, these new materials and methods provide access to colloidal crystals that incorporate particles with the well-established designer properties of MOFs and, therefore, increase the scope of possibilities for colloidal crystal engineering with DNA.
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http://dx.doi.org/10.1038/s41467-020-16339-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237412PMC
May 2020

Controlling the DNA Hybridization Chain Reaction.

J Am Chem Soc 2020 05 1;142(19):8596-8601. Epub 2020 May 1.

Department of Chemistry and International Institute for Nanotechnology, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States.

A novel method for controlling the oligomerization of metastable DNA hairpins using the hybridization chain reaction (HCR) is reported. Control was achieved through the introduction of a base-pair mismatch in the duplex of the hairpins. The mismatch modification allows one to kinetically differentiate initiation versus propagation events, leading to DNA oligomers up to 10 monomers long and improving dispersities from 2.5 to 1.3-1.6. Importantly, even after two consecutive chain extensions, dispersity remained unaffected, showing that well-defined block co-oligomers can be achieved. As a proof-of-concept, this technique was then applied to hairpin monomers functionalized with a mutant green fluorescent protein to prepare protein oligomers. Taken together, this work introduces an effective method for controlling living macromolecular HCR oligomerization in a manner analogous to the controlled polymerization of small molecules.
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http://dx.doi.org/10.1021/jacs.0c02892DOI Listing
May 2020
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