If a solution of DNA-coated nanoparticles is allowed to crystallize, the thermodynamic structure can be predicted by a set of structural design rules analogous to Pauling's rules for ionic crystallization. The details of the crystallization process, however, have proved more difficult to characterize as they depend on a complex interplay of many factors. Here, we report that this crystallization process is dictated by the individual DNA bonds and that the effect of changing structural or environmental conditions can be understood by considering the effect of these parameters on free oligonucleotides. Specifically, we observed the reorganization of nanoparticle superlattices using time-resolved synchrotron small-angle X-ray scattering in systems with different DNA sequences, salt concentrations, and densities of DNA linkers on the surface of the nanoparticles. The agreement between bulk crystallization and the behavior of free oligonucleotides may bear important consequences for constructing novel classes of crystals and incorporating new interparticle bonds in a rational manner.DNA materials | self assembly | nanostructure M aterials scientists have accomplished much by studying the way atoms and molecules crystallize. In these systems, however, the identity of the atom and its bonding behavior cannot be independently controlled, limiting our ability to tune material properties at will. In contrast, when a nanoparticle is modified with a dense shell of upright, oriented DNA, it can behave as a programmable atom equivalent (PAE) (1, 2) that can be used to synthesize diverse crystal structures with independent control over composition, scale, and lattice symmetry (3-14). The thermodynamic product of this crystallization process has been extensively studied by both experimental and theoretical means, and thus a series of design rules has been proposed and validated with a simple geometric model known as the complementary contact model (CCM). These rules allow one to predict the thermodynamically favored structure as the arrangement of particles that maximizes complementary contacts and therefore DNA hybridization (2, 6). These efforts have been very successful in predicting the thermodynamically favored product; recent studies have even demonstrated that PAEs can form single-crystal Wulff polyhedra that are analogous to those formed in atomic systems with the same crystallographic symmetry (15). However, the fact that there is a crystalline thermodynamic product does not mean that any choice of DNA and nanoparticles will result in crystalline systems in practice (3, 4). For example, crystallization has been observed for a relatively narrow class of PAEs (16) and in a manner that is primarily dependent upon the length of the DNA linker and temperature at which assembly occurs (8). Thus, absent from our understanding of these systems is a connection between the crystallization process and the properties of the DNA bonds that form the foundation of these structures.Here, we study the crystallization process and find t...

Herein, we report an example of entropy-driven crystallization behavior in DNA-nanoparticle superlattice assembly, marking a divergence from the well-established enthalpic driving force of maximizing nearest-neighbor hybridization connections. Such behavior is manifested in the observation of a non-close-packed, body-centered cubic (bcc) superlattice when using a system with self-complementary DNA linkers that would be predicted to form a close-packed, face-centered cubic (fcc) structure based solely on enthalpic considerations and previous design rules for DNA-linked particle assembly. Notably, this unexpected phase behavior is only observed when employing long DNA linkers with unpaired "flexor" bases positioned along the length of the DNA linker that increase the number of microstates available to the DNA ligands. A range of design conditions are tested showing sudden onsets of this behavior, and these experiments are coupled with coarse-grained molecular dynamics simulations to show that this entropy-driven crystallization behavior is due to the accessibility of additional microstates afforded by using long and flexible linkers.

Chemical bonds are a key determinant of the structure and properties of a material. Thus, rationally designing arbitrary materials requires complete control over the bond. While atomic bonding is dictated by the identity of the atoms, nanoparticle superlattice engineering, where nano-particle “atoms” are held together by DNA “bonds”, offers a route to design crystal lattices in a way that nature cannot: through altering the oligonucleotide bond. Herein, the use of RNA, as opposed to DNA, is explored by synthesizing superlattices in which nanoparticles are bonded by DNA/DNA, RNA/RNA, and DNA/RNA duplexes. By moving beyond nanoparticle superlattices assembled only with DNA, a new degree of freedom is introduced, providing programmed responsiveness to enzymes and greater bond versatility. Therefore, the oligonucleotide bond can have programmable function beyond dictating the structure of the material and moves nanoparticle superlattices closer to naturally occurring biomaterials, where the line between structural and functional elements is blurred.

Complementary tetrahedral small molecule-DNA hybrid (SMDH) building blocks have been combined to form nucleic acid-based polymeric nanoparticles without the need for an underlying template or scaffold. The sizes of these particles can be tailored in a facile fashion by adjusting assembly conditions such as SMDH concentration, assembly time, and NaCl concentration. Notably, these novel particles can be stabilized and transformed into functionalized spherical nucleic acid (SNA) structures through the incorporation of capping DNA strands conjugated with functional groups. These results demonstrate a systematic, efficient strategy for the construction and surface functionalization of well-defined, size-tunable nucleic acid particles from readily accessible molecular building blocks. Furthermore, because these nucleic acid-based polymeric nanoparticles exhibited enhanced cellular internalization and resistance to DNase I compared to free synthetic nucleic acids, they should have a plethora of applications in diagnostics and therapeutics.

Small molecule–DNA hybrids can be synthesized in a one-pot fashion and in good yields by coupling multiazide cores to alkyne-modified DNAs on a solid support using click chemistry.