The properties and behavior of chemical systems often change when their size is reduced below a certain threshold. My research involves designing and synthesizing hierarchical materials from sub-nanometer to micron scales (e.g. from atomic clusters to nanoparticles to nanoparticle assemblies). The focus is to understand how structure impacts function so that we can engineer chemical constructs for applications in chemistry (chemical analysis), biology (imaging), and medicine (diagnostics and drug delivery).

A new DNA-based nanostructure allows the chemical analysis of live cells using DNA and proteins

The ability to detect analytes in live cells is key to understanding fundamental biological processes and disease progression. DNA and protein-based methods are routinely used to study cellular analytes, but these techniques cannot be applied to living cells because neither DNA nor proteins efficiently enter cells. We have developed a new class of highly tailorable intracellular probes based on protein spherical nucleic acids (ProSNAs) that comprise a protein core modified with a dense shell of oligonucleotides. These constructs have emergent properties, such as, enhanced cellular uptake and increased protease- and nuclease-resistance, which make them superior probes compared to the native form of their constituents. Importantly, both the DNA and the protein can be used as recognition elements. As examples, we have shown binding-based detection of intracellular pH using an i-motif as the recognition element and activity-based sensing of intracellular glucose using glucose oxidase as the protein core. ProSNAs are resistant to false-positive signal, allow amplified sensing through enzymatic reactions, and result in >120-fold fluorescence turn on in buffer. Moreover, they allow analyte detection intracellularly with high specificity and sensitivity. Going forward, these constructs can be potentially used to study dynamic biological processes, detect diseases early based on intracellular markers, and screen drugs in high throughput.

DNA can be used to build hierarchical, dynamic crystals of nanoparticles

Spherical nucleic acids (SNAs), nanoparticles functionalized with a dense shell of radially oriented oligonucleotides, are powerful building blocks for synthesizing hierarchical materials through DNA-mediated bottom-up assembly. SNAs can be analogized as programmable atom equivalents (PAEs) in which the nanoparticle core is the “atom” and the DNA forms the programmable “bond”. Unlike atomic systems, PAEs allow the atom and bond to be varied independently. Therefore, by changing the nanoparticle size, shape, and composition and the DNA sequence, length, and density, a rich phase-space of matter can be accessed. By modulating the DNA length post-synthetically, a new class of dynamic metamaterials can be accessed. Inspired by positively charged histone proteins that condense DNA in the nuclei of cells, we have developed a chemical approach that uses multivalent metal cations to induce the contraction and re-expansion of the DNA bonds. During this process, the interparticle distances can be controlled with sub-nanometric precision. The metal ion-responsive changes in DNA structure lead to >65% change in the volume of the crystal while maintaining crystallinity. This new approach represents a powerful strategy to alter superlattice structure and stability, which can impact diverse applications through dynamic control of material properties, including optical, magnetic, and mechanical properties. Our publication on this work was featured as the front cover of Journal of the American Chemical Society.

Unlike bulk water, aqueous microdroplets are chemically reactive

Bulk water serves as an inert solvent for many chemical/biological reactions. We discovered that reactions in micron-sized droplets of water can be starkly different from bulk, both in terms of rates as well as pathways. For example, we observed that gold nanoparticles (AuNPs) form spontaneously from metal precursors in aqueous microdroplets and self-assemble to form nanowires, representing the first example of self-assembly without using added ligands, templates, or electric fields. Compared to bulk synthesis, the size and growth rate of AuNPs are enhanced by 2- and 100,000-fold, respectively, in microdroplets. Our publication on this work was one of the top 50 most read Nature Communications articles in chemistry and materials science in 2018.

The unusual redox phenomena also apply to various small biomolecules, such as pyruvate, lipoic acid, fumarate, and oxaloacetate, which undergo spontaneous redox reactions without any added electron donors/acceptors or applied voltage. Importantly, while none of these reactions proceeds spontaneously in bulk water, redox efficiencies can reach >90% in microdroplets. These remarkable findings highlight the significance of size and confinement on chemical reactivity and demonstrate that aqueous microdroplets have a unique environment that could be potentially used as powerful microreactors for synthesizing various compounds and nanomaterials. Importantly, these results also suggest that reactions that occur inside micron-scale cellular vessels composed of 70% water but are inferred from bulk properties may need re-evaluation.

Conducting polymers can be used to develop wirelessly controlled drug release systems

Programmable and controllable delivery of drugs creates an avenue for personalized medicine yet remains one of the main challenges in drug administration today. My thesis work was focused on developing an electroresponsive drug delivery system (DDS) as a solution to this problem. The DDS consists of drug-loaded polypyrrole nanoparticles (PPy NPs) that undergo changes in redox state upon electric stimulation, releasing their drug cargo with spatiotemporal precision. We demonstrated that by tuning the nanoparticle composition, various drugs ranging from small molecules such as piroxicam, an arthritis medication, to polypeptides such as insulin can be released in a pulsed manner by applying nominal voltages (<1 V). Moreover, by incorporating metallic elements into the PPy scaffold, we developed an improved DDS that can release drugs at unprecedented low voltages (50-75 mV). The widened window of operating voltage allows the release of methotrexate, an anti-cancer drug susceptible to redox degradation at higher voltages, with retained bioactivity. In collaboration with the Annes Lab (Stanford Medicine), we showed through in vivo studies that the bioactivity of the released drug is retained. In collaboration with the Arbabian Lab (Stanford Engineering), we demonstrated that drug release can be triggered wirelessly through acoustic excitation using a millimeter-sized piezoelectric transducer. Taken together, these results represent a cornerstone towards developing minimally invasive implants which can treat various chronic diseases.

Halogens can be arranged into hierarchical structures called super- and hyperhalogens with extremely high electron affinities

Superhalogens are traditionally metal-halogen complexes with electron affinities far exceeding that of chlorine, the element with the highest electron affinity. Until 2011, superhalogens had been known to the chemistry community for over 30 years and all superhalogens studied in this time were based on either the octet-rule or the 18-electron rule. We designed two new classes of superhalogens, one that is based on the Wade-Mingo's rule, well-known for descibing the stability of closeo-boranes, and one that is based on pseudohalogens in place of halogens. These molecules represent the first examples of superhalogens with neither a metal atom nor a halogen atom. Our design rules provide access to a previously unexplored class of superhalogens and hyperhalogens. Subsequently, we computationally demonstrated that the strong oxidizing property of superhalogens can be leveraged to promote new and unusual chemistry (e.g. stabilizing a hitherto unknown +III oxidation state of Zn or forcing otherwise noble gas compounds to form metastable compounds). Moreover, I investigated the potential of superhalogens for designing high energy density salts, hypersalts with high capacity for hydrogen storage, and ligands with increased binding affinity to biological receptors.