(3cp) DNA and Protein-Based Emergent Nanomaterials for Precision Medicine

Materials with reduced dimensions often have properties that are different from the bulk. These properties are typically manifested when the sizes of the materials are below ~100 nm length scales, although in some cases unusual behavior can be observed on the microscale. My graduate and postdoctoral work has been focused on designing, synthesizing, and studying the behavior of nanomaterials, with an emphasis on utilizing their properties for biological applications.

My independent research program will be focused on the synthesis of DNA and protein-based nanomaterials to address diagnostic and therapeutic challenges in precision medicine. Recent work has shown that these materials can have emergent properties useful for biological applications. Specifically, three main directions of my lab will be to (1) synthesize novel architectures and investigate their physico-chemical properties and interactions with living systems, (2) develop protein and DNA-based chemical probes for bioimaging and bioanalysis, and (3) investigate how the structure of DNA and protein-based nanomaterials can be modulated for efficacious gene and protein therapy. This research program builds on my expertise in nanomaterial synthesis, live-cell chemical analysis, and fabrication of controlled drug release systems gained through my academic training. Given the highly interdisciplinary nature of the proposed research, this program will provide training opportunities for doctoral students and postdoctoral scholars from various backgrounds, including chemical engineering, chemistry, materials science, and biomedical engineering.

Research Experience

I have worked in collaboration with physicists, chemists, engineers, and medical doctors, and published 21 articles in total (12 as first author).

Postdoctoral research with Prof. Chad A. Mirkin at Northwestern University

Protein spherical nucleic acids for live-cell chemical analysis. The chemical analysis of live cells at the molecular level can provide fundamental insight into dynamic cellular processes, inform about the role of intracellular analytes in disease progression, and guide the development of new medical diagnostic tools. Nucleic acid-based structures are particularly attractive as probes due to the unparalleled architectural control afforded by them. By using aptamers, oligonucleotide sequences that bind to target analytes with high selectivity and sensitivity, it is possible to detect a wide variety of analytes, provided the binding event can be transduced into a signaling event. I have developed a new class of signaling aptamers called “FIT-aptamers”. These aptamers contain a visco-sensitive dye which is forced to intercalate or FIT between base pairs upon target binding, turning the fluorescence on due to restricted rotation of the dye. The FIT strategy reduces false positive signals common to all fluorophore-quencher systems, provides up to 20-fold fluorescence enhancement upon target binding, and allows target detection down to nanomolar concentrations in complex milieu such as human serum.

However, linear nucleic acids do not enter cells efficiently and are rapidly degraded by nucleases which limits their use live cells. Densely functionalizing these nucleic acids onto a nanoparticle core results in a spherical nucleic acid (SNA) which has emergent properties, including the ability to enter cells, resistance to nuclease degradation, and in some cases, 100-fold enhanced binding to targets. I have developed a new class of intracellular probes based on protein SNAs (ProSNAs) which use a protein as the nanoparticle core. The ProSNA architecture allows the intracellular delivery of functional proteins and offers protease resistance, enabling analyte detection via the highly programmable nucleic acid shell or a functional protein core.

SNAs as stimuli-responsive synthons. In addition to their remarkable biological properties, SNAs can be used as programmable material building blocks for the synthesis of hierarchically ordered materials. The nanoparticles can be conceptualized as artificial “atoms” and the DNA as programmable “bonds”. Inspired by positively charged histone proteins that condense DNA in the nuclei of cells, I 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 leads to >65% changes 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 the optical, magnetic, and mechanical properties.

Graduate research with Prof. Richard N. Zare at Stanford University

Electroresponsive nanoparticles for drug delivery on demand. 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. I demonstrated that by tuning the nanoparticle composition, various drugs ranging from small molecules such as methotrexate, an anti-cancer drug, to polypeptides such as insulin can be released in a pulsed manner by applying unprecedented low voltages (50-75 mV). 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.

Unusual and accelerated reactions in aqueous microdroplets. 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.

Teaching Interests

Interests. Given my multifaceted background, I am well-suited to teach a broad range of courses. My ideal teaching program would be focused on teaching upper-level undergraduate classes or specialized topic courses for graduate students, including Design of Drug Delivery and Diagnostic Systems, Molecular Engineering, Separation Science, Soft Matter and Interfacial Phenomena, and Chemical Kinetics.

Experience. During my academic training, I have been significantly involved in teaching and mentoring. As an undergraduate student, I tutored ~20 underprivileged children in Math and English for free for two years. As a graduate student, I taught 6 different courses to undergraduate students in both lab and lecture-based settings. I also designed and taught my own courses through the Stanford Splash! program to ~130 high school students. My most enjoyable teaching experience has been as a research mentor to 13 students. These students have been from different majors (3 chemical engineering, 4 chemistry, 1 biomedical engineering, and 5 high school). Additionally, during my postdoc, I have been advising a team of ~20 graduate students, postdoctoral fellows, and undergraduates as the leader of the Anisotropic Nanomaterials Subgroup in the Mirkin Lab.

Outcome. I have been highly appreciated by my students for my teaching and mentoring. Notably, 12 of my mentees are currently pursuing science-related degrees/careers and have gone on to win state and national science talent searches, prestigious graduate fellowships, and research awards.

Funding

International Institute for Nanotechnology Postdoctoral Fellowship ($75,000/year), 2019

AIChE Women in Chemical Engineering Travel Award ($1,000), 2019

HHMI Hanna Gray Fellow Finalist ($10,000), 2019

Winston Chen Stanford Graduate Fellowship (~$75,000/year), 2015-2017

Center for Molecular Analysis and Design Fellowship at Stanford (~$75,000/year), 2013-2015

Global Innovation Festival 2016 Travel Award from DGIST, South Korea ($2,000), 2016

I have also assisted Prof. Zare at Stanford University and Prof. Mirkin at Northwestern University in writing multi-PI proposals resulting in >$15 million in funding from the NIH and DOE.

Selected Publications

* equal contribution

• Samanta, D.*; Ebrahimi, S. B.*; Mirkin, C. A. Adv. Mater. 2020.
• Samanta, D.; Iscen, A.; Laramy, C. R.; Ebrahimi, S. B.; Bujold, K. E.; Schatz, G. C.; Mirkin, C. A. J. Am. Chem. Soc. 2019.
• Ebrahimi, S. B.*; Samanta, D.*; Cheng, H. F.; Nathan, L. I.; Mirkin, C. A. J. Am. Chem. Soc. 2019.
• Ebrahimi, S. B.; Samanta, D.; Mirkin, C. A. J. Am. Chem. Soc. 2020.
• Lee, J. K.; Samanta, D.; Nam, H. G.; Zare, R. N. Nat. Commun. 2018.
• Lee, J. K.; Samanta, D.; Nam, H. G.; Zare, R. N. J. Am. Chem. Soc. 2019.