DNA Dendrons as Agents for Intracellular Delivery

Distler, Max E; Teplensky, Michelle H.; Bujold, Katherine E.; Kusmierz, Caroline D.; Evangelopoulos, Michael; Mirkin, Chad A.

doi:10.1021/jacs.1c07240

Cited by 34 publications

(34 citation statements)

References 57 publications

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“…Now, an efficient strategy is required to functionalize cargo with DNA of a precise valency and sequence predetermined to have optimized binding strength to the gating DNA, in order to apply this approach to more practically relevant cargo that often possess complex structures. Inspired by how nature has evolved a ubiquitous nuclear localization sequence (NLS) to tag proteins for import into the cell nucleus, 49 we developed a DNA dendron 50 as a universal tag for the selective transport of complex macromolecules (Figure 4a). This DNA dendron (denoted as D6-P5) was synthesized to have a six-branch geometry at the 5′ end where each branch features a 5′-CTACG-3′ sequence that forms a 5-bp hybridized region with the gating DNA and a reactive handle at its 3′ end for functionalization of cargo (see the complete sequence in SI, Section 2).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

A General DNA-Gated Hydrogel Strategy for Selective Transport of Chemical and Biological Cargos

Distler

Cheng

et al. 2021

J. Am. Chem. Soc.

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The selective transport of molecular cargo is critical in many biological and chemical/materials processes and applications. Although nature has evolved highly efficient in vivo biological transport systems, synthetic transport systems are often limited by the challenges associated with fine-tuning interactions between cargo and synthetic or natural transport barriers. Herein, deliberately designed DNA−DNA interactions are explored as a new modality for selective DNA-modified cargo transport through DNA-grafted hydrogel supports. The chemical and physical characteristics of the cargo and hydrogel barrier, including the number of nucleic acid strands on the cargo (i.e., the cargo valency) and DNA−DNA binding strength, can be used to regulate the efficiency of cargo transport. Regimes exist where a cargo−barrier interaction is attractive enough to yield high selectivity yet high mobility, while there are others where the attractive interactions are too strong to allow mobility. These observations led to the design of a DNA-dendron transport tag, which can be used to universally modify macromolecular cargo so that the barrier can differentiate specific species to be transported. These novel transport systems that leverage DNA−DNA interactions provide new chemical insights into the factors that control selective cargo mobility in hydrogels and open the door to designing a wide variety of drug/probe-delivery systems.

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Section: ■ Results and Discussionmentioning

confidence: 99%

A General DNA-Gated Hydrogel Strategy for Selective Transport of Chemical and Biological Cargos

Distler

Cheng

et al. 2021

J. Am. Chem. Soc.

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“…Using various branching phosphoramidites, , DNA dendrons were synthesized with three, four, or six branches ( b Dn, the number of branches, b = 3, 4, or 6) (Figure a), each featuring single-stranded sticky ends (5′ TTCCTT 3′) that can hybridize with AuNP PAEs bearing complementary sticky ends (5′ AAGGAA 3′) (Figure b). The dendrons have an 18- to 26-base stem that hybridizes with the arms on a template, enabling one to control the distance between the branches and the dendrimer core.…”

Section: Results and Discussionmentioning

confidence: 99%

Nanoparticle Superlattices through Template-Encoded DNA Dendrimers

et al. 2021

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The chemical interactions that lead to the emergence of hierarchical structures are often highly complex and difficult to program. Herein, the synthesis of a series of superlattices based upon 30 different structurally reconfigurable DNA dendrimers is reported, each of which presents a well-defined number of single-stranded oligonucleotides (i.e., sticky ends) on its surface. Such building blocks assemble with complementary DNA-functionalized gold nanoparticles (AuNPs) to yield five distinct crystal structures, depending upon choice of dendrimer and defined by phase symmetry. These DNA dendrimers can associate to form micelledendrimers, whereby the extent of association can be modulated based upon surfactant concentration and dendrimer length to produce a low-symmetry Ti 5 Ga 4 -type phase that has yet to be reported in the field of colloidal crystal engineering. Taken together, colloidal crystals that feature three different types of particle bonding interactionstemplate−dendron, dendrimer−dendrimer, and DNA−modified AuNP-dendrimerare reported, illustrating how sequence-defined recognition and dynamic association can be combined to yield complex hierarchical materials.

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“…In fact, if one follows this supposition to a logical end point, one concludes that the ultimate vaccine structures will be modular, nanoscale in size, and molecularly pure where the position and connectivity of every atom has been optimized for signaling control and therapeutic efficacy. This is where molecularly precise entities like peptide-functionalized dendrimers may play a significant role. , …”

Section: Discussionmentioning

confidence: 99%

Rational Vaccinology: Harnessing Nanoscale Chemical Design for Cancer Immunotherapy

Huang¹,

Callmann²,

Wang³

et al. 2022

ACS Cent. Sci.

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Cancer immunotherapy is a powerful treatment strategy that mobilizes the immune system to fight disease. Cancer vaccination is one form of cancer immunotherapy, where spatiotemporal control of the delivery of tumor-specific antigens, adjuvants, and/or cytokines has been key to successfully activating the immune system. Nanoscale materials that take advantage of chemistry to control the nanoscale structural arrangement, composition, and release of immunostimulatory components have shown significant promise in this regard. In this Outlook, we examine how the nanoscale structure, chemistry, and composition of immunostimulatory compounds can be modulated to maximize immune response and mitigate off-target effects, focusing on spherical nucleic acids as a model system. Furthermore, we emphasize how chemistry and materials science are driving the rational design and development of next-generation cancer vaccines. Finally, we identify gaps in the field that should be addressed moving forward and outline future directions to galvanize researchers from multiple disciplines to help realize the full potential of this form of cancer immunotherapy through chemistry and rational vaccinology.

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DNA Dendrons as Agents for Intracellular Delivery

Cited by 34 publications

References 57 publications

A General DNA-Gated Hydrogel Strategy for Selective Transport of Chemical and Biological Cargos

A General DNA-Gated Hydrogel Strategy for Selective Transport of Chemical and Biological Cargos

Nanoparticle Superlattices through Template-Encoded DNA Dendrimers

Rational Vaccinology: Harnessing Nanoscale Chemical Design for Cancer Immunotherapy

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