Research in our lab relevant to the COVID-19 outbreak
We have recently focused our team's expertise on the challenges faced with the coronavirus pandemic, to see where we might leverage our research on nanoparticle-based treatments of bacterial infections for the treatment of COVID19 infections. In our current NIH-funded project, “Infection-homing nanosystems as antibacterial therapeutics-delivery platforms”, we discovered a nanoparticle therapeutic that can rescue animals with lethal bacterial (Staph aureus and Pseudomonas aeruginosa) lung infections. We think that this approach may also be effective with viral infections. The approach was motivated by the observation that many lung infections are lethal because they trigger an over-reaction of the immune system. Cells from the immune system known as macrophages normally respond to an infection by generating inflammation. This inflammation signals the rest of the immune system to mount its defense. However, sometimes in lung infections the inflammatory response is too great, and this over-reaction of the immune cells in the lungs inflames the air sacs in one or both lungs, filling them with fluids and sending the patient into a critical state. The mode of action of our nanosystem is to deliver a gene therapeutic (siRNA against the IRF5 gene) that reprograms pro-inflammatory immune cells (macrophages) to temporarily suppress their inflammatory immune response in the lungs. In mouse models of lethal bacterial pneumonia, we have found that this treatment gives the animals time to mount an effective endogenous immune response. All of animals who had lethal bacterial lung infections could be rescued with this approach, which is described in (Kim, B.; et al., "Immunogene therapy with fusogenic nanoparticles modulates macrophage response to Staphylococcus aureus," Nat. Commun.2018, 9, 1969). The approach is enabled by two breakthroughs: the discovery of a nanoparticle system that can effectively avoid endocytosis and deliver the gene therapeutic into cells, and a targeting peptide (CRV) that makes the nanoparticle specific for the macrophage cells that need to be suppressed (J. Vis. Exp.2019, (146); Adv. Mater.2019, 49, 1903637).
Because it harnesses the body’s own immune response, we hypothesize that our nanosystem will also be effective for a range of viral lung infections. The area we hope to explore will be to see if we can suppress the inflammatory over-reaction to viral infections in the lungs, with the hope of rescuing patients who enter the critical stage of the disease. We are currently engaging with leading viral infectious disease experts, and hope to soon be testing the system in viral influenza and/or COVID19 animal models. We are also engaging with industrial partners to position the materials manufacturing processes for clinical translation.
Researchers: Qinglin Yang, Ruhan Fan, Sanahan Vijayakumar. Collaboration with Sangeeta Bhatia at MIT and Erkki Ruoslahti at SBPMDI.
Infection-homing nanosystems as antibacterial therapeutics-delivery platforms
Staphylococcus aureus and Pseudomonas aeruginosa are the leading causes of hospital-acquired infections and contribute significantly to morbidity and mortality. Standard treatment of infection entails repetitive high-dose administrations of antibiotics, but the treatment is often rendered ineffective due to poor delivery to sites of infection and drug resistance mechanisms preventing antibiotic access to intracellular drug targets (e.g. the drug impermeable cell wall in gram-negative P. aeruginosa). Skin infections that have invaded down to the muscles and fibers are also difficult to reach by free-antibiotic formulations and require surgical treatment. This project aims to use nanoparticles to attack this problem in two ways: (1) improve the efficacy of existing antibiotics with targeted nanoparticle formulations; and (2) develop more effective means to deliver gene therapeutics that can overcome obstacles encountered by existing antibiotics. For the conventional antibiotics, we hypothesize that loading them into longer-circulating nanovehicles that will home to sites of infection and subsequently facilitate drug uptake into cells/bacteria of interest can overcome resistance. For the newly emergent gene therapeutics, we hypothesize that loading them into longer-circulating nanovehicles and homing them to immune cells will allow more effective reprogramming of the cells to improve their ability to fight off bacterial infections. This project is engineering two nanoplatforms: (1) peptide-based agents that can selectively penetrate the bacterial membrane (i.e. peptide permeation agents) to which small molecule drugs will be tethered for increased uptake and (2) porous silicon nanoparticles (pSiNP) to load drugs that have poor delivery to sites of infection or to immune cells due to unfavorable physicochemical properties (hydrophobic, highly ionic, endosomal uptake, etc). These nanoplatforms will be targeted to sites of infection using peptides we have previously discovered or additional peptides being identified in the course of this research. Model drugs with poor in vivo antibacterial activity will be loaded and optimal platforms selected based on drug loading, release kinetics, and cellular uptake for in vivo pharmacokinetics. Finally, we will focus on the therapeutic performance of leading nanoplatform candidates in vivo. The goal is to demonstrate the biosafety and therapeutic efficacy (i.e. bacterial burden clearance, tissue recovery, improved survival) of the nanosystems. This project brings together a multi-disciplinary team of experts in basic research, translational investigation, and clinical medicine: Dr. Erkki Ruosalhti (Sanford-Burnham Medical Research Institute, SBMRI), Dr. Sangeeta N. Bhatia (MIT), and the Sailor lab at UCSD.
Self-Activating Porous Nanomaterials for Chemical Sampling and Storage
This project is part of the IARPA Ithildin program, which intends to develop novel sorbent materials for chemical sampling and storage. The project uses mesoscale silicon to provide "smart" sorbents that preferentially adsorb target chemicals or chemical classes while rejecting high-abundance clutter materials, such as water or hydrocarbons. Designed in collaboration with Profs. Seth Cohen and Akif Tezcan and engineered in collaboration with Leidos inc., the materials incorporate MOF and bio-MOF components with the capability to activate or deactivate the sorbent material based on specific stimuli. Harnessing the photonic properties of the silicon nanomaterial host, the composite materials present a remotely detectable optical signature indicative of adsorption of a specific target or target class.
Porous Silicon Nanoparticle/Polycaprolactone Composite Nanofibers for Nervous System Repair
There are more than 17,000 new cases of spinal cord injury (SCI) reported in the US each year. Traumatic injuries that result in damage to peripheral nerves affects more than 20 million patients in the US, and each year more than 100,000 patients in the US and Europe undergo surgical procedures to repair peripheral nerve damage. Surgeries to repair peripheral nerve damage are reported to give less than 50% recovery of motor and sensory function, and for direct injuries to the spinal cord, there is at present no clinical treatment that can completely restore lost function. This project aims to address the problem by developing nanomaterials that can be surgically implanted to aid the body in healing severed or crushed neuronal connections. Among the promising nerve regeneration strategies, nanofiber scaffolds are of intense interest. However, current nanofiber technologies lack the ability to fully repair the injured nervous system. This is in part due to the complex interplay of mechanical, biochemical, and biological factors associated with neuronal regrowth, and our limited understanding of this process. This project aims to develop and test biodegradable porous silicon nanoparticle/polymer composite nanofibers with the capability of providing the appropriate physical and chemical cues to regrowing neurons. In order to provide chemical cues that could be used to guide neuronal repair, we plan to incorporate drug-loaded porous silicon nanoparticles into nanofibers. It is difficult to incorporate sensitive therapeutics (such as proteins, siRNA, etc.) into nanofibers due to the volatile solvents that are used in their fabrication. Porous silicon nanoparticles can protect and deliver sensitive biological therapeutics, and they can be used to alter the degradation rate of nanofiber scaffolds. The project aims to develop next-generation nanofiber scaffolds as regenerative substrates to enhance the growth of extending neurites. This project brings together a multi-disciplinary team of experts in basic research, translational investigation, and clinical medicine: Dr. Erkki Ruosalhti (Sanford-Burnham Medical Research Institute, SBMRI), Dr. Mark Tuszynski (UC San Diego School of Medicine), and the Sailor lab at UCSD.
Sponsor: NSF-Division of Division of Chemical, Bioengineering, Environmental, and Transport Systems (CBET-1603177)
Sponsored by the US National Science Foundation, the SSSiN is an immersive six-week workshop on the preparation, characterization, and applications of porous silicon-based nanomaterials. Provides training of incoming graduate students, undergraduates, visiting scholars, and high school students from around the world.
Although the scope of our work at the University is limited to basic research into the fundamental properties of materials, many of the concepts developed in our labs have been translated to products and processes in the commercial world. Any commercial products and processes that emerge from our fundamental discoveries are outside the course and scope of our University-related employment; however, we actively encourage transition of technologies to the commercial sector with the assistance of UCSD’s Office of Innovation and Commercialization