Qiaobing Xu

Bio: Qiaobing Xu is an academic researcher from Tufts University. The author has contributed to research in topics: Genome editing & Medicine. The author has an hindex of 42, co-authored 139 publications receiving 7951 citations. Previous affiliations of Qiaobing Xu include Massachusetts Institute of Technology & Harvard University.

Preparation of monodisperse biodegradable polymer microparticles using a microfluidic flow-focusing device for controlled drug delivery.

Abstract: Degradable microparticles have broad utility as vehicles for drug delivery and form the basis of several therapies approved by the US Food and Drug Administration. Conventional emulsion-based methods of manufacturing produce particles with a wide range of diameters (and thus kinetics of release) in each batch. This paper describes the fabrication of monodisperse, drug-loaded microparticles from biodegradable polymers using the microfluidic flow-focusing (FF) devices and the drug-delivery properties of those particles. Particles are engineered with defined sizes, ranging from 10 microm to 50 microm. These particles are nearly monodisperse (polydispersity index = 3.9%). A model amphiphilic drug (bupivacaine) is incorporated within the biodegradable matrix of the particles. Kinetic analysis shows that the release of the drug from these monodisperse particles is slower than that from conventional methods of the same average size but a broader distribution of sizes and, most importantly, exhibit a significantly lower initial burst than that observed with conventional particles. The difference in the initial kinetics of drug release is attributed to the uniform distribution of the drug inside the particles generated using the microfluidic methods. These results demonstrate the utility of microfluidic FF for the generation of homogenous systems of particles for the delivery of drugs.

Efficient delivery of genome-editing proteins using bioreducible lipid nanoparticles

Abstract: A central challenge to the development of protein-based therapeutics is the inefficiency of delivery of protein cargo across the mammalian cell membrane, including escape from endosomes. Here we report that combining bioreducible lipid nanoparticles with negatively supercharged Cre recombinase or anionic Cas9:single-guide (sg)RNA complexes drives the electrostatic assembly of nanoparticles that mediate potent protein delivery and genome editing. These bioreducible lipids efficiently deliver protein cargo into cells, facilitate the escape of protein from endosomes in response to the reductive intracellular environment, and direct protein to its intracellular target sites. The delivery of supercharged Cre protein and Cas9:sgRNA complexed with bioreducible lipids into cultured human cells enables gene recombination and genome editing with efficiencies greater than 70%. In addition, we demonstrate that these lipids are effective for functional protein delivery into mouse brain for gene recombination in vivo. Therefore, the integration of this bioreducible lipid platform with protein engineering has the potential to advance the therapeutic relevance of protein-based genome editing.

Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents

Abstract: Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1Bth allele into the cochlea of neonatal Tmc1Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1Bth/+ mice. These findings suggest that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.

Pericellular Hydrogel/Nanonets Inhibit Cancer Cells†

Abstract: Fibrils formed by proteins are vital components for cells. However, selective formation of xenogenous nanofibrils of small molecules on mammalian cells has yet to be observed. Here we report an unexpected observation of hydrogel/nanonets of a small D-peptide derivative in pericellular space. Surface and secretory phosphatases dephosphorylate a precursor of a hydrogelator to trigger the self-assembly of the hydrogelator and to result in pericellular hydrogel/nanonets selectively around the cancer cells that overexpress phosphatases. Cell-based assays confirm that the pericellular hydrogel/nanonets block cellular mass exchange to induce apoptosis of cancer cells, including multidrug-resistance (MDR) cancer cells, MES-SA/Dx5. Pericellular hydrogel/nanonets of small molecules to exhibit distinct functions illustrates a fundamentally new way to engineer molecular assemblies spatiotemporally in cellular microenvironment for inhibiting cancer cell growth and even metastasis.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Light Propagation with Phase Discontinuities: Generalized Laws of Reflection and Refraction

Abstract: Conventional optical components rely on gradual phase shifts accumulated during light propagation to shape light beams. New degrees of freedom are attained by introducing abrupt phase changes over the scale of the wavelength. A two-dimensional array of optical resonators with spatially varying phase response and subwavelength separation can imprint such phase discontinuities on propagating light as it traverses the interface between two media. Anomalous reflection and refraction phenomena are observed in this regime in optically thin arrays of metallic antennas on silicon with a linear phase variation along the interface, which are in excellent agreement with generalized laws derived from Fermat’s principle. Phase discontinuities provide great flexibility in the design of light beams, as illustrated by the generation of optical vortices through use of planar designer metallic interfaces.

Localized Surface Plasmon Resonance Spectroscopy and Sensing

Abstract: Localized surface plasmon resonance (LSPR) spectroscopy of metallic nanoparticles is a powerful technique for chemical and biological sensing experiments. Moreover, the LSPR is responsible for the electromagnetic-field enhancement that leads to surface-enhanced Raman scattering (SERS) and other surface-enhanced spectroscopic processes. This review describes recent fundamental spectroscopic studies that reveal key relationships governing the LSPR spectral location and its sensitivity to the local environment, including nanoparticle shape and size. We also describe studies on the distance dependence of the enhanced electromagnetic field and the relationship between the plasmon resonance and the Raman excitation energy. Lastly, we introduce a new form of LSPR spectroscopy, involving the coupling between nanoparticle plasmon resonances and adsorbate molecular resonances. The results from these fundamental studies guide the design of new sensing experiments, illustrated through applications in which researchers use both LSPR wavelength-shift sensing and SERS to detect molecules of chemical and biological relevance.

Cancer nanomedicine: progress, challenges and opportunities.

Abstract: The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem from the complexities and heterogeneity of tumour biology, an incomplete understanding of nano-bio interactions and the challenges regarding chemistry, manufacturing and controls required for clinical translation and commercialization. This Review highlights the progress, challenges and opportunities in cancer nanomedicine and discusses novel engineering approaches that capitalize on our growing understanding of tumour biology and nano-bio interactions to develop more effective nanotherapeutics for cancer patients.

Analysis of nanoparticle delivery to tumours

Abstract: This Perspective explores and explains the fundamental dogma of nanoparticle delivery to tumours and answers two central questions: ‘how many nanoparticles accumulate in a tumour?’ and ‘how does this number affect the clinical translation of nanomedicines?’