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Gene Editing in Utero via Non-Viral, Lipid Nanoparticle Delivery of mRNA Complexes

Researchers at the University of California, Davis have developed a new method of in utero gene editing through lipid nanoparticle delivery of mRNA gene editors.

Sequential Targeting and Crosslinking Nanoparticles for Tackling the Multiple Barriers to Treat Brain Tumors

Researchers at the University of California, Davis have developed an approach to improve drug delivery to tumors and metastases in the brain. Their multi-barrier tackling delivery strategy has worked to efficiently impact brain tumor management while also achieving increased survival times in anti-cancer efficacy.

(SD2022-180) Method of viral nanoparticle functionalization for therapy and imaging applications

Plant viral nanoparticles (plant VNPs) are promising biogenetic nanosystems for the delivery of therapeutic, immunotherapeutic, and diagnostic agents. The production of plant VNPs is simple and highly scalable through molecular farming in plants. Some of the important advances in VNP nanotechnology include genetic modification, disassembly/reassembly, and bioconjugation. Although effective, these methods often involve complex and time-consuming multi-step protocols.

Systems and Methods for Scaling Electromagnetic Apertures, Single Mode Lasers, and Open Wave Systems

The inventors have developed a scalable laser aperture that emits light perpendicular to the surface. The aperture can, in principal, scale to arbitrarily large sizes, offering a universal architecture for systems in need of small, intermediate, or high power. The technology is based on photonic crystal apertures, nanostructured apertures that exhibit a quasi-linear dispersion at the center of the Brillouin zone together with a mode-dependent loss controlled by the cavity boundaries, modes, and crystal truncation. Open Dirac cavities protect the fundamental mode and couple higher order modes to lossy bands of the photonic structure. The technology was developed with an open-Dirac electromagnetic aperture, known as a Berkeley Surface Emitting Laser (BKSEL).  The inventors demonstrate a subtle cavity-mode-dependent scaling of losses. For cavities with a quadratic dispersion, detuned from the Dirac singularity, the complex frequencies converge towards each other based on cavity size. While the convergence of the real parts of cavity modes towards each other is delayed, going quickly to zero, the normalized complex free-spectral range converge towards a constant solely governed by the loss rate of Bloch bands. The inventors show that this unique scaling of the complex frequency of cavity modes in open-Dirac electromagnetic apertures guarantees single-mode operation of large cavities. The technology demonstrates scaled up single-mode lasing, and confirmed from far-field measurements. By eliminating limits on electromagnetic aperture size, the technology will enable groundbreaking applications for devices of all sizes, operating at any power level. BACKGROUND Single aperture cavities are bounded by higher order transverse modes, fundamentally limiting the power emitted by single-mode lasers, as well as the brightness of quantum light sources. Electromagnetic apertures support cavity modes that rapidly become arbitrarily close with the size of the aperture. The free-spectral range of existing electromagnetic apertures goes to zero when the size of the aperture increases. As a result, scale-invariant apertures or lasers has remained elusive until now.  Surface-emitting lasers have advantages in scalability over commercially widespread vertical-cavity surface-emitting lasers (VCSELs). When a photonic crystal is truncated to a finite cavity, the continuous bands break up into discrete cavity modes. These higher order modes compete with the fundamental lasing mode and the device becomes more susceptible to multimode lasing response as the cavity size increases. 

Transformable Smart Peptides as Cancer Therapeutics

Researchers at the University of California, Davis have developed smart, supramolecular, materials that can assemble into nanoparticles. These particles can then be used to target tumor cells.

Nanopore Sequencing of RNA Using Reverse Transcription

This invention demonstrates that an engineered cellular reverse transcriptase is a potent motor protein that can processively thread single-stranded RNA (ssRNA) through the MspA biological nanopore in single nucleotide steps while it is synthesizing cDNA. Notably, this represents a first-ever achievement for threading of ssRNA through the engineered Mycobacterium smegmatis porin A (MspA) nanopore in discrete steps, and also for ssRNA sequencing with the MspA nanopore. The inventors constructed the “quadromer map” for ssRNA in the MspA nanopore, which is essentially a table that can convert measured nanopore ion current to RNA sequences, using ssRNAs of known sequences. In addition, the inventors discovered that the single-molecule kinetic rates of the reverse transcriptase are affected by the presence of stable RNA secondary structures. Monitoring this biophysical behavior can be used to determine RNA structures during nanopore sequencing.  Nanopore sequencing is a powerful third generation sequencing technology that offers advantages such as ultra-long read length and direct detection of chemically modified bases. One of the key components of developing a successful nanopore sequencer is identifying potent motor proteins (such as polymerases or helicases) that can thread single-stranded (ss) DNA or ssRNA through the nanopore in discrete steps with high processivity.   

Guided Template Based Electrokinetic Microassembly (TEA)

Researchers at the University of California, Irvine have developed a guided electrokinetic assembly technique that utilizes dielectrophoretic and electroosmotic forces for micro- and nanomanufacturing. This technique provides a new way for assembling microelectronics and living cells for tissue engineering applications.

Peptides for Macromolecular Delivery

This invention includes: 1) Applying amphiphilic peptides (AP) (e.g. E5-TAT, INF7-TAT, or similar peptides) in novel scenarios for delivering CRISPR-Cas9 RNPs and performing genome editing in primary human cells of substantial clinical value (human pluripotent stem cells [HSPCs], T cells) and mouse neuronal progenitor cells in vitro or in vivo. These peptides have also been used for delivering plasmid DNA as a DNA vaccine into human cells in culture, and into mouse tissue in vivo to produce a robust immune response.  2) Novel peptide sequences (derivatives of E5-TAT or INF7-TAT) with improved properties and/or improved activity (relative to the founder peptides) in delivering cargo into target cells. The inventors have created a library of related sequences, all with distinct activity in delivering cargo to different cell types. These novel peptide sequences have been applied to the same scenarios as above, with improved outcomes compared to the parent peptides, E5-TAT or INF7-TAT, in genome editing, and may provide benefits in delivery of plasmid DNA as well. This is especially valuable when delivering to cell types that are notoriously difficult to transduce, such as HSPCs and T cells, leading to new therapeutic opportunities. Background Biological macromolecules offer great potential as therapeutics but the greatest hurdle that remains is their efficient cell entry into target cell types. Cell entry is limiting for two very promising technologies, DNA vaccines and genome editing, and this invention aims to address the unmet need. DNA vaccines would provide a rapid and inexpensive approach to vaccination for a wide range of viral pathogens, but have been hampered by poor delivery of the DNA into the target cells, resulting in an immune response not potent enough for effective vaccination. DNA vaccines involve delivering a plasmid which encodes a viral protein into the nucleus of human cells, where it can be transcribed and then expressed to be recognized by the immune system. In order to improve their efficacy, DNA vaccines have been delivered via in vivo electroporation, a painful process that requires specialized equipment and repeat dosing. Genome editing holds immense therapeutic promise for correcting the genetic mutations underlying disease, or for preventing or treating non-genetic disease. Delivery of the genome editing enzymes, such as CRISPR-Cas9, into the cytosol or nuclei of cells in need of manipulation remains the largest hurdle. Delivering CRISPR-Cas9 as a ribonucleoprotein (RNP) complex offers many advantages compared to other approaches (e.g. the use of viral vectors or lipid nanoparticles), but the RNP lacks an inherent method of cell entry. Amphiphilic peptides (AP) enable transduction of macromolecules into cells and therefore the inventors have aimed to apply APs to delivering cargo such as CRISPR-Cas9 RNPs as well as plasmid DNA into target cell types. The activity of a specific AP in delivering cargo into a the cytosol of a cell is often dependent on the specific cargo being delivered as well as the specific cell type. Therefore, the inventors have created libraries of related APs with diversity in their amino acid sequence in order to allow delivery of macromolecular cargo to a range of cell types, dependent on the specific application. A peptide sequence derived from influenza hemagluttinin sequence, HA2, has been previously described and applied as an endosomolytic peptide (ELP). When the HA2 sequence is appended with TAT, a positively charged cell penetrating peptide sequence derived from the HIV TAT protein, the fusion peptide “HA2-TAT” is able to deliver macromolecular cargo across the cell membrane and also act as an ELP to allow endosomal escape. Derivatives of the HA2-TAT sequence with changes in the amino acid sequence of the peptide, such as the peptide “E5-TAT,” has improved properties compared to HA2-TAT in solubility as well as delivering cargo into cells. The INF7-TAT peptide has similar properties, where INF7 is another glutamine-rich analog of HA2 with improved properties for endosomal escape. HA2 and its derivates (E5, INF7) with and without fusion to cell penetrating peptides (HA2-TAT, E5-TAT, INF7-TAT) have been applied to delivering macromolecular cargo such as proteins and nucleic acids into cells.

Nanocellulose-based Aerogel Fibers as Insulation

Researchers at the University of California, Davis have produced continuous, sheath-core, coaxial fibers with highly porous, nanocellulose, aerogel cores for use as high-performance insulators.

DNA-based, Read-Only Memory (ROM) for Data Storage Applications

Researchers at the University of California, Davis have collaborated with colleagues at the University of Washington and Emory University to develop a DNA-based, memory and data storage technology that integrates seamlessly with semiconductor-based technologies and conventional electronic devices.

Nanopore Sensor to Characterize Nano and Microscale Particles and Cells

Researchers at the University of California, Riverside can discriminate between mixed populations of cells and particles in solution using pressure to displace objects across a nanopore multiple times.  Ionic current flow through the nanopore indicates the pressure required to translocate the object in the pore, which correlates to the object’s mass and volume.  Key to these results is that a nanopore sensor allows pressure oscillations to capture and release repeatedly the same object to learn about its inertia and morphology.  Such data can provide details about the size and shape of analytes, their morphologies and structural constraints, or even pathological conditions of living cells. Fig. 1 Nanopore sensing of differently sized cells in a mixed bacterial culture.  

Precision Graphene Nanoribbon Wires for Molecular Electronics Sensing and Switch

The inventors have developed a highly scalable multiplexed approach to increase the density of graphene nanoribbon- (GNR) based transistors. The technology forms a single device/chip (scale to 16,000 to >1,000,000 parallel transistors) on a single integrated circuit for single molecule biomolecular sensing, electrical switching, magnetic switching, and logic operations. This work relates to the synthesis and the manufacture of molecular electronic devices, more particularly sensors, switches, and complimentary metal-oxide semiconductor (CMOS) chip-based integrated circuits.Bottom-up synthesized graphene nanoribbons (GNRs) have emerged as one of the most promising materials for post-silicon integrated circuit architectures and have already demonstrated the ability to overcome many of the challenges encountered by devices based on carbon nanotubes or photolithographically patterned graphene. The new field of synthetic electronics borne out of GNRs electronic devices could enable the next generation of electronic circuits and sensors.  

Bioengineered Wnt5a Therapeutics For Advanced Cancers

Researchers at the University of California, Davis have developed RNA-based therapeutics to treat Wnt5A-expressing cancers, including treatment-resistant prostate cancer.

Foliar Formulation to Protect Plants from Abiotic Stress

Prof. Juan Pablo Giraldo and his colleagues from the University of California, Riverside have developed a foliar formulation for increasing crop protection and photosynthetic performance when crops are under light, heat, and salinity stress. This is achieved by applying a nanomaterial (poly (acrylic acid) nanoceria, PNC) that interacts with plant chloroplasts to reduce abiotic stress. The nanoparticle formulation uses a novel, scalable and biocompatible approach to protect plant seeds, seedlings, and mature plants from stress.  The emerging field of nano-enabled agriculture has the potential to create crops that are protected from climate change induced stresses and have enhanced photosynthesis.   Fig 1: a, Nanoceria (PNC) increases photosynthesis and biomass in Arabidopsis plants under stress. No nanoparticles (NNP) are shown as control. b, Substantial damage to Arabidopsis plants exposed to excess light was mitigated by PNC.  

Ultrastable Nanoemulsions In Disordered And Ordered States

Researchers in the Department of Chemistry and Biochemistry at UCLA have developed a method for the production of crystalline, iridescent emulsions stable to repeated dilutions.

Zinc Nanocomposites And Stents For Functional Applications

UCLA researchers in the Department of Mechanical Engineering have developed a method to manufacture zinc-based metal matrix nanocomposites (MMNCs) for functional applications, such as stents.

Methods To Modulate Size, Malleability, And Biodistribution Of Cell-Based Therapeutics

While some cell therapies have experienced success, many current cell therapies fall short in that enough cells do not reach the target tissue and/or the cells are incapable of producing clinically relevant thresholds of desired products sufficient to impact the disease state. Consequently, there is a major fundamental need to genetically engineer therapeutic cells to be more effective and robust using integrating viruses and powerful gene editing technologies like CRISPR, which can target ten to hundreds of genes simultaneously. However, this is highly problematic because the process of genetic engineering introduces dangerous unwanted mutations into the genome that can lead to cancer and other life-threatening diseases, especially if such cells permanently engraft into the body or fuse with host cells, which is common with stem cells. Therefore, the FDA does not readily permit the introduction of new genetic material or the extensive alteration of endogenous genes in cell-based therapies with the exception of CAR-T cells. For this reason, there is a major underlying need in the cell therapy sector to genetically enhance therapeutic cells to express gene products encoding biologics and then render them safe prior to clinical use.

Bioengineered Let-7c Therapy for HCC Treatment

Researchers at the University of California, Davis have developed a bioengineered, RNA-based treatment for advanced liver cancer and hepatocellular carcinoma (HCC).

Exosome-Mimicking Nanovesicles

Researchers at the University of California, Davis have developed a method of synthesizing stem cell-derived, exosome-mimicking, nanovesicles that have the therapeutic potential to rescue apoptotic neurons in culture.

Single Conjugative Vector for Genome Editing by RNA-guided Transposition

The inventors have constructed conjugative plasmids for intra- and inter-species delivery and expression of RNA-guided CRISPR-Cas transposases for organism- and site-specific genome editing by targeted transposon insertion. This invention enables integration of large, customizable DNA segments (encoded within a transposon) into prokaryotic genomes at specific locations and with low rates of off-target integration.

Biomimetic Conductive Hydrogels

UCLA researchers in the Department of Bioengineering have developed a novel electrically conductive scaffold system with a hyaluronic acid (HA)-based hydrogel for biomimetic research to treat spinal cord and other central nervous system (CNS) injuries.

New Classes Of Cage And Polyhedron And New Classes Of Nanotube And Nanotube With Planar Faces

UCLA researchers have developed a novel algorithm that can be used to design unique self-assembled molecules and nanostructures.

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