Nanostructured Gyroid Cubic Lipid Phases Containing Functional RNA Molecules: Pore Forming Lipids Facilitate Release of RNA Through Cellular Membranes Cyrus R. Safinya, University of California-Santa Barbara, DMR Figure 1. The gyroid lipid cubic phase incorporating functional RNA within its two (green and orange) water channels. A lipid bilayer surface separates the two intertwined but independent water channels. For clarity, the bilayer (which has an unusual saddle-splay shape) is represented by a surface (gray) corresponding to a thin layer in the center of the membrane as indicated in the enlarged inset. The novel structure, termed Q II G, siRNA, was derived by use of synchrotoron x-ray scattering methods at the Stanford Synchrotron Radiation Laboratory. (Adapted from C. Leal et al., J. Am. Chem. Soc. 2010, 132, 16841, DOI: /ja , and Langmuir 2011, 27, DOI: /la200679x) /ja /la200679x The use of cationic lipids as biomimetic synthetic carriers of nucleic acids in cell-based delivery applications is currently unprecedented. The range of applications dependent on efficient nucleic acid delivery ranges from therapeutics (with DNA genes) to functional genomics and biotechnology (with gene silencing RNA). Nevertheless, our ability to design lipid-carriers of nucleic acids, able to enter cells by punching holes in the membranes of internal cellular components (which trap the carriers upon cell entry), is the current limiting step in the development of gene delivery/gene silencing technology. Employing a physicochemical approach our study led to the discovery of a method to produce a novel bicontinuous gyroid cubic lipid phase, which incorporates functional RNA molecules for gene silencing (Figure 1). The complex structure of the Gyroid Cubic phase was derived by our group using state-of-the-art synchrotron x-ray scattering methods at the National Facility at the Stanford Synchrotron Radiation Laboratory. The paper demonstrates the remarkable properties of the lipid cubic phase-RNA complex in efficient cell delivery and sequence- specific gene silencing. This significant finding is consistent with the hypothesis that cubic phase lipids have pore forming abilities because of their unusual “saddle-splay” membrane shape (gray surface in Figure 1). The work was reported in the Journal of the American Chemical Society and Langmuir (C. Leal et al., JACS 2010, 132, 16841, and Langmuir 2011, 27, 7691–7697).

Education and Outreach Research Training: A Biomolecular Materials Emphasis Cyrus R. Safinya, University of California-Santa Barbara, DMR Education: Undergraduate and graduate students, and postdoctoral scholars with backgrounds in materials science, physics, chemistry, and biology, are educated in methods to discover nature’s rules for assembling molecular building blocks in distinct shapes and sizes for particular functions. The learned concepts enable development of advanced nanoscale materials for broad potential applications in electronic, chemical, and pharmaceutical industries. Outreach/Participation of undergraduate and underrepresented students: Visiting graduate student Janos Kayser participated in experimental studies of the structure and phase behavior of Keratins (an important intermediate filament) with Joanna Deek. Janos is currently obtaining his PhD degree from the Technical University of Munich under the supervision of Professor Andreas Bausch who spent a short sabbatical in our group. (For more information see Julia Korolenko (left, top photo), a recent undergraduate transfer student from Santa Barbara City College (and a former INSET intern (Internships in Nanosystems, Science, Engineering, and Technology) with our group) is now engaged in research training while simultaneously pursuing her undergraduate degree in Chemistry and Biochemistry at UCSB. She is being trained, by Chemistry graduate student Joanna Deek (2nd from left, top photo), in studies invovling the structure and phase behavior of mixtures of nuerofilaments and microtubules, which mimic the cytoskeletal proteins of neurons. Thomas Oyuela-Trachter (right, top photo), a senior undergraduate student at UCSB (Molecular, Cellular, & Developmental Biology Depart.), participated in the CAMP (California Alliance for Minority Participation) summer internship program. He was mentored by physics graduate student Peter Chung (second from right, top photo). His project focused on the real-space imaging of microtubule-tau protein complexes, which might elucidate interactions critical to understanding neuron axonal growth and diseases like Alzheimer's related to tau-protein malfunction. Jose Lopez (right, bottom photo, pictured with physics graduate student Ramsey Majzoub), a UCSB undergraduate student majoring in Mechanical Engineering, worked for three quarters in the group (under the mentorship of Dr. Youli Li, Manager of the MRL X-ray Facility) helping with design and construction of a new SAXS instrument to characterize nanoscale assemblies. He is starting graduate school this Fall at San Diego State University.