Publications by authors named "Yuanyu Huang"

61 Publications

Advances of mRNA vaccines for COVID-19: A new prophylactic revolution begins.

Asian J Pharm Sci 2021 May 22;16(3):263-264. Epub 2021 Mar 22.

Institute of Engineering Medicine, Advanced Research Institute of Multidisciplinary Science, School of Life Science, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing 100081, China.

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http://dx.doi.org/10.1016/j.ajps.2021.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261073PMC
May 2021

Identification of SARS-CoV-2-against aptamer with high neutralization activity by blocking the RBD domain of spike protein 1.

Signal Transduct Target Ther 2021 06 10;6(1):227. Epub 2021 Jun 10.

School of Life Science; Advanced Research Institute of Multidisciplinary Science; Institute of Engineering Medicine; Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing, China.

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http://dx.doi.org/10.1038/s41392-021-00649-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190169PMC
June 2021

Microarray investigation of glycan remodeling during macrophage polarization reveals α2,6 sialic acid as an anti-inflammatory indicator.

Mol Omics 2021 May 18. Epub 2021 May 18.

Institutes of Biomedical Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, 200032, China.

Glycosylation is a widely occurring posttranslational modification. Here, we applied a quick, convenient and high-throughput strategy (lectin array) to investigate the variation in glycans on different macrophage subtypes derived from THP-1 and RAW264.7 cells. For THP-1 cells, there were more significant differences in the glycan on M2 macrophages compared to the other two subtypes. In contrast, M1 macrophages exhibited more significant glycan remodeling than the other subtypes for the RAW264.7 cell line. The response of the lectins which recogonize the N-glycan and α2,6 sialic acid was higher during polarization into anti-inflammatory phase (THP-1 derived M2 subtypes), and lower in pro-inflammatory phase (RAW264.7 M1 subtypes). The regulation of several α2,6 sialyltransferase genes was coincident with the regulation of the α2,6 sialic acid on the two cell lines. The lectin response and glycosyltranferase gene expression confirmed that α2,6 sialic acid showed higher expression in the anti-inflammatory phase. This indicated that α2,6 sialic acid was a potential indicator for the anti-inflammatory response.
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http://dx.doi.org/10.1039/d0mo00192aDOI Listing
May 2021

siRNA Design and GalNAc-Empowered Hepatic Targeted Delivery.

Methods Mol Biol 2021 ;2282:77-100

School of Life Science, Advanced Research Institute of Multidisciplinary Science, and Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing, China.

Small interfering RNA (siRNA) is a clinically approved therapeutic modality, which has attracted widespread attention not only from basic research but also from pharmaceutical industry. As siRNA can theoretically modulate any disease-related gene's expression, plenty of siRNA therapeutic pipelines have been established by tens of biotechnology companies. The drug performance of siRNA heavily depends on the sequence, the chemical modification, and the delivery of siRNA. Here, we describe the rational design protocol of siRNA, and provide some modification patterns that can enhance siRNA's stability and reduce its off-target effect. Also, the delivery method based on N-acetylgalactosamine (GalNAc)-siRNA conjugate that is widely employed to develop therapeutic regimens for liver-related diseases is also recapitulated.
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http://dx.doi.org/10.1007/978-1-0716-1298-9_6DOI Listing
June 2021

Effective Enrichment Strategy Using Boronic Acid-Functionalized Mesoporous Graphene-Silica Composites for Intact N- and O-Linked Glycopeptide Analysis in Human Serum.

Anal Chem 2021 05 20;93(17):6682-6691. Epub 2021 Apr 20.

The Fifth People's Hospital, Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.

The heterogeneity and low abundance of protein glycosylation present challenging barriers to the analysis of intact glycopeptides, which is key to comprehensively understanding the role of glycosylation in an organism. Efficient and specific enrichment of intact glycopeptides could help greatly with this problem. Here, we propose a new enrichment strategy using a boronic acid (BA)-functionalized mesoporous graphene-silica composite (denoted as [email protected]) for isolating intact glycopeptides from complex biological samples. The merits of this composite, including high surface area and synergistic effect from size exclusion functionality of mesoporous material, hydrophilic interaction of silica, and the reversible covalent binding with BA, enable the effective and specific enrichment of both intact N- and O-glycopeptides. The results from the enrichment performance of the strategy evaluated by standard glycoproteins and the application to global N- and O-glycosylation analyses in human serum indicate the robustness and potential of the strategy for intact glycopeptide analysis.
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http://dx.doi.org/10.1021/acs.analchem.0c05482DOI Listing
May 2021

Puromycin-Modified Silica Microsphere-Based Nascent Proteomics Method for Rapid and Deep Nascent Proteome Profile.

Anal Chem 2021 04 15;93(16):6403-6413. Epub 2021 Apr 15.

Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, P.R. China.

Nascent proteome is crucial in directly revealing how the expression of a gene is regulated on a translation level. In the nascent protein identification, puromycin capture is one of the pivotal methods, but it is still facing the challenge in the deep profiling of nascent proteomes due to the low abundance of most nascent proteins. Here, we describe the synthesis of puromycin-modified silica microspheres (PMSs) as the sorbent of dispersive solid-phase microextraction and the establishment of the PMS-based nascent proteomics (PMSNP) method for efficient capture and analysis of nascent proteins. The modification efficiency of puromycin groups on silica microspheres reached 91.8% through the click reaction. After the optimization and simplification of PMSNP, more than 3500 and 3900 nascent proteins were rapidly identified in HeLa cells and mouse brains within 13.5 h, respectively. The PMSNP method was successfully applied to explore changes in the translation process in a biological stress model, namely, the lipopolysaccharide-stimulated HeLa cells. Biological functional analyses revealed the unique characters of the nascent proteomes and exhibited the superiority of the PMSNP in the identification of low abundance and secreted nascent proteins, thus demonstrating the sensitivity and immediacy of the PMSNP method.
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http://dx.doi.org/10.1021/acs.analchem.0c05393DOI Listing
April 2021

A Near-Infrared-II Polymer with Tandem Fluorophores Demonstrates Superior Biodegradability for Simultaneous Drug Tracking and Treatment Efficacy Feedback.

ACS Nano 2021 03 9;15(3):5428-5438. Epub 2021 Mar 9.

Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry Chinese Academy of Sciences, Beijing 100190, China.

NIR-II (1000-1700 nm) fluorescence imaging is continually attracting strong research interest. However, current NIR-II imaging materials are limited to small molecules with fast blood clearance and inorganic nanomaterials and organic conjugated polymers of poor biodegradability and low biocompatibility. Here, we report a highly biodegradable polyester carrying tandem NIR-II fluorophores as a promising alternative. The polymer encapsulated a platinum intercalator (56MESS, (5,6-dimethyl-1,10-phenanthroline) (1,2-diaminocyclohexane) platinum(II)) and was conjugated with both a cell-targeting RGD peptide and a caspase-3 cleavable peptide probe to form nanoparticles for simultaneous NIR-II and apoptosis imaging. , the nanoparticles were approximately 4-1000- and 1.5-10-fold more potent than cisplatin and 56MESS, respectively. Moreover, , they significantly inhibited tumor growth on a multidrug-resistant patient-derived mouse model (PDX). Finally, through label-free laser desorption-ionization mass spectrometry imaging (MALDI-MSI), 56MESS release in the deeper tumors was observed. This work highlighted the use of biodegradable NIR-II polymers for monitoring drugs and therapeutic effect feedback in real-time.
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http://dx.doi.org/10.1021/acsnano.1c00076DOI Listing
March 2021

Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA.

Nano Lett 2021 04 17;21(8):3680-3689. Epub 2021 Feb 17.

School of Life Science, Advanced Research Institute of Multidisciplinary Science, Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing 100081, China.

Efficient endosomal escape is the most essential but challenging issue for siRNA drug development. Herein, a series of quaternary ammonium-based amphiphilic triblock polymers harnessing an elaborately tailored pH-sensitive hydrophobic core were synthesized and screened. Upon incubating in an endosomal pH environment (pH 6.5-6.8), mPEG-P(DPA--DMAEMA)-PT (PDDT, the optimized polymer) nanomicelles (PDDT-Ms) and PDDT-Ms/siRNA polyplexes rapidly disassembled, leading to promoted cytosolic release of internalized siRNA and enhanced silencing activity evident from comprehensive analysis of the colocalization and gene silencing using a lysosomotropic agent (chloroquine) and an endosomal trafficking inhibitor (bafilomycin A1). In addition, PDDT-Ms/siPLK1 dramatically repressed tumor growth in both HepG2-xenograft and highly malignant patient-derived xenograft models. PDDT-Ms-armed siPD-L1 efficiently blocked the interaction of PD-L1 and PD-1 and restored immunological surveillance in CT-26-xenograft murine model. PDDT-Ms/siRNA exhibited ideal safety profiles in these assays. This study provides guidelines for rational design and optimization of block polymers for efficient endosomal escape of internalized siRNA and cancer therapy.
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http://dx.doi.org/10.1021/acs.nanolett.0c04468DOI Listing
April 2021

Nano-herb medicine and PDT induced synergistic immunotherapy for colon cancer treatment.

Biomaterials 2021 02 5;269:120654. Epub 2021 Jan 5.

School of Life Sciences, Tianjin University, Tianjin Engineering Center of Micro Nano Biomaterials and Detection Treatment Technology, Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, 300072, China. Electronic address:

A variety of therapies have been developed and used for the treatment of colon cancer, however, the high mortality rate remains high and more effective strategies are still in urgent needs. In this study, an immunotherapy approach that is composed of innate immune activator Astragaloside III (As) and the photodynamic therapy (PDT) reagent chlorine e6 (Ce6) ((As + Ce6)@MSNs-PEG), was developed for colon cancer treatment. We showed that (As + Ce6)@MSNs-PEG could effectively activate NK cells and inhibit the proliferation of tumor cells in vitro. It could also effectively reach tumor sites, induce infiltration of immune cells into the tumor, and enhance the cytotoxicity of natural killer cells and CD8 T cells in vivo. Without obvious side effects, (As + Ce6)@MSNs-PEG treatment significantly inhibited tumor growth and extended the lifespan of tumor-bearing mice. Further results revealed that treatment of (As + Ce6)@MSNs-PEG led to enhanced IFN secretion by immune cells and increased T-box transcription factor (T-bet), which is highly expressed by T cells. Therefore, (As + Ce6)@MSNs-PEG may serve as an effective and safe platform for combinatory use with nano-herb medicine and PDT to provide a new therapy for colon cancer treatment.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120654DOI Listing
February 2021

Harnessing pH-Sensitive Polycation Vehicles for the Efficient siRNA Delivery.

ACS Appl Mater Interfaces 2021 Jan 6;13(2):2218-2229. Epub 2021 Jan 6.

College of Pharmacy, Xinxiang Medical University, 453003 Xinxiang, P.R. China.

pH-sensitive hydrophobic segments have been certificated to facilitate siRNA delivery efficiency of amphiphilic polycation vehicles. However, optimal design concepts for these vehicles remain unclear. Herein, by studying the library of amphiphilic polycations mPEG-PAMA-P(DEA--D5A) (EAE5), we concluded a multifactor matching concept (p values, "proton buffering capacities" (BCs), and critical micelle concentrations (CMCs)) for polycation vehicles to improve siRNA delivery efficiency and . We identified that the stronger BCs in a pH 5.5-7.4 subset induced by EAE5 (p = 6.79) and EAE5 (p = 6.20) are effective for siRNA delivery . Further, the stronger BCs occurred in a narrow subset of pH 5.5-6.5 and the lower CMC attributed to higher siRNA delivery capacity of EAE5 than EAE5 after intravenous administration and subcutaneous injection. More importantly, 87.2% gene knockdown efficacy was achieved by EAE5 subcutaneous injection, which might be useful for an mRNA vaccine adjuvant. Furthermore, EAE5 also successfully delivered siRRM2 to tumor intravenous administration and received highly efficient antitumor activity. Taken together, the suitable p values, strong BCs occurred in pH 5.5-6.5, and low CMCs were probably the potential solution for designing efficient polycationic vehicles for siRNA delivery.
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http://dx.doi.org/10.1021/acsami.0c17866DOI Listing
January 2021

Surface Charge of Supramolecular Nanosystems for In Vivo Biodistribution: A MicroSPECT/CT Imaging Study.

Small 2020 09 14;16(37):e2003290. Epub 2020 Aug 14.

Aix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), UMR 7325, Equipe Labellisée Ligue Contre le Cancer, Marseille, 13288, France.

Bioimaging has revolutionized medicine by providing accurate information for disease diagnosis and treatment. Nanotechnology-based bioimaging is expected to further improve imaging sensitivity and specificity. In this context, supramolecular nanosystems based on self-assembly of amphiphilic dendrimers for single photon emission computed tomography (SPECT) bioimaging are developed. These dendrimers bear multiple In radionuclides at their terminals as SPECT reporters. By replacing the macrocyclic 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid cage with the smaller 1,4,7-triazacyclononane-1,4,7-triacetic acid scaffold as the In chelator, the corresponding dendrimer exhibits neutral In -complex terminals in place of negatively charged In -complex terminals. This negative-to-neutral surface charge alteration completely reverses the zeta-potential of the nanosystems from negative to positive. As a consequence, the resulting SPECT nanoprobe generates a highly sought-after biodistribution profile accompanied by a drastically reduced uptake in liver, leading to significantly improved tumor imaging. This finding contrasts with current literature reporting that positively charged nanoparticles have preferential accumulation in the liver. As such, this study provides new perspectives for improving the biodistribution of positively charged nanosystems for biomedical applications.
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http://dx.doi.org/10.1002/smll.202003290DOI Listing
September 2020

Efficient hepatic delivery and protein expression enabled by optimized mRNA and ionizable lipid nanoparticle.

Bioact Mater 2020 Dec 13;5(4):1053-1061. Epub 2020 Jul 13.

School of Life Science, Advanced Research Institute of Multidisciplinary Science, Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing, 100081, China.

mRNA is a novel class of therapeutic modality that holds great promise in vaccination, protein replacement therapy, cancer immunotherapy, immune cell engineering However, optimization of mRNA molecules and efficient delivery are quite important but challenging for its broad application. Here we present an ionizable lipid nanoparticle (iLNP) based on iBL0713 lipid for and expression of desired proteins using codon-optimized mRNAs. mRNAs encoding luciferase or erythropoietin (EPO) were prepared by transcription and formulated with proposed iLNP, to form iLP171/mRNA formulations. It was revealed that both luciferase and EPO proteins were successfully expressed by human hepatocellular carcinoma cells and hepatocytes. The maximum amount of protein expression was found at 6 h post-administration. The expression efficiency of EPO with codon-optimized mRNA was significantly higher than that of unoptimized mRNA. Moreover, no toxicity or immunogenicity was observed for these mRNA formulations. Therefore, our study provides a useful and promising platform for mRNA therapeutic development.
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http://dx.doi.org/10.1016/j.bioactmat.2020.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355334PMC
December 2020

Induction of lipid droplets in THP-1 macrophages by multi-walled carbon nanotubes in a diameter-dependent manner: A transcriptomic study.

Toxicol Lett 2020 Oct 7;332:65-73. Epub 2020 Jul 7.

Key Laboratory of Environment-Friendly Chemistry and Application of Ministry of Education, Lab of Biochemistry, College of Chemistry, Xiangtan University, Xiangtan 411105, PR China. Electronic address:

Exposure to multi-walled carbon nanotubes (MWCNTs) might induce lipid droplet (LD) biogenesis, but the roles of physicochemical properties of MWCNTs, as well as the mechanisms, remain poorly understood. In this study, we investigated lipid laden foam formation in THP-1 macrophages exposed to MWCNTs of different diameters, and attempted transcriptomic analysis to study the possible mechanisms. We observed diameter-dependent cytotoxicity, lipid accumulation and intracellular reactive oxygen species production that were more pronounced for MWCNTs with smaller diameters compared with those with larger diameters. However, more MWCNTs with larger diameters were retained in macrophages after 24 h exposure. One possible explanation for the inverse relationship between MWCNT bio-effects and internalization is that macrophages altered the expression of exocytotic genes to export toxic MWCNTs. Transcriptomic data showed that MWCNTs with smaller diameters more effectively altered the expression of genes related with cytotoxicity and lipid metabolism, and KEGG pathway analysis suggested that MWCNTs with smaller diameters activated peroxisome proliferator-activated receptor (PPAR) signalling pathway (map03320), leading to over-expression of perilipin 2, the surface proteins of LDs. Western blot confirmed that MWCNTs effectively promoted CD36, PPARγ and perilipin 2, key components in map03320. Moreover, inhibition of PPARγ by chemicals or siRNA significantly inhibited lipid accumulation induced by MWCNTs with smaller diameters, and perilipin 2 proteins in MWCNT-exposed macrophages could be decreased by PPARγ siRNA. In conclusion, the results of this study revealed the induction of LDs by MWCNTs in a diameter-dependent manner through the activation of PPAR signalling pathway.
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http://dx.doi.org/10.1016/j.toxlet.2020.07.007DOI Listing
October 2020

Boronic acid-functionalized mesoporous magnetic particles with a hydrophilic surface for the multimodal enrichment of glycopeptides for glycoproteomics.

Analyst 2020 Aug 3;145(15):5252-5259. Epub 2020 Jul 3.

Institutes of Biomedical Sciences & Minhang hospital, Fudan University, Shanghai, 200032, China.

Glycosylation is an important mechanism of secondary protein processing. Large-scale profiling of glycopeptides released by proteolytic digestion of glycoproteins from biologic samples with complex compositions is limited due to their low abundance. Herein, we present a multimodal material based on boronic acid-modified mesoporous magnetic particles with a hydrophilic surface and enlarged pores around 10 nm. Multimodal enrichment successfully improved the enrichment specificity and efficiency of BMMP by synergistic interaction of hydrophilicity and boronic acid functional groups. The 10 nm pore size allows glycopeptides to enter the channel. Hydrophilic glycopeptides could be selectively enriched with an extremely low limit of detection (0.33 fmol per μL) and a high selectivity (1 : 100). From 2 μL of human serum, 328 unique glycopeptides from 101 glycoproteins were identified. A total of 33% of those glycoproteins overlapped with FDA-cleared blood serum biomarkers. It is expected that BMMP in the future can be used for large-scale biomedical glycoproteomics studies.
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http://dx.doi.org/10.1039/d0an00648cDOI Listing
August 2020

ROS-Activatable siRNA-Engineered Polyplex for NIR-Triggered Synergistic Cancer Treatment.

ACS Appl Mater Interfaces 2020 Jul 9;12(29):32289-32300. Epub 2020 Jul 9.

School of Life Science; Advanced Research Institute of Multidisciplinary Science; Institute of Engineering Medicine; Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing 100081, P. R. China.

Small interfering RNA (siRNA) shows excellent pharmaceutical prospects in treating diverse life-threatening diseases. Photodynamic therapy (PDT) is a clinically employed noninvasive treatment method that can trigger selective damage toward targeted tissue and cells. However, insufficient delivery of siRNA and photosensitizer to cancer cells remarkably hindered the application of siRNA and PDT in the treatment of cancer. In this study, a unique reactive oxygen species (ROS)-activatable polyplex, which consists of the PEGylated cationic polymer, ROS-cleavable linker, photosensitizer Ce6, and RRM2-against siRNA, termed PPTC/siRNA, was engineered. Upon irradiation of near-infrared (NIR) light, the polyplex efficiently generated ROS, which triggered degradation of the ROS-sensitive linker, disassembling the complex, destabilization of the cell membrane, and significantly accelerated cellular entry and endosomal escape of siRNA. Besides achieving effective siRNA internalization and gene silence in cancer cells , PPTC/siRNA synergistically inhibited tumor growth in both cell line-derived xenograft and patient-derived xenograft hepatocellular carcinoma murine models by repressing the RRM2 expression (reducing cell proliferation) and triggering photodynamic killing (enhancing cell apoptosis). The proposed polyplex also showed ideal safety profiles both in cell line and in animal. It provides a novel strategy for NIR-triggered RNAi and PDT combinational cancer treatment.
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http://dx.doi.org/10.1021/acsami.0c06614DOI Listing
July 2020

Therapeutic siRNA: state of the art.

Signal Transduct Target Ther 2020 06 19;5(1):101. Epub 2020 Jun 19.

Chinese Academy of Sciences (CAS), Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 100190, Beijing, People's Republic of China.

RNA interference (RNAi) is an ancient biological mechanism used to defend against external invasion. It theoretically can silence any disease-related genes in a sequence-specific manner, making small interfering RNA (siRNA) a promising therapeutic modality. After a two-decade journey from its discovery, two approvals of siRNA therapeutics, ONPATTRO (patisiran) and GIVLAARI™ (givosiran), have been achieved by Alnylam Pharmaceuticals. Reviewing the long-term pharmaceutical history of human beings, siRNA therapy currently has set up an extraordinary milestone, as it has already changed and will continue to change the treatment and management of human diseases. It can be administered quarterly, even twice-yearly, to achieve therapeutic effects, which is not the case for small molecules and antibodies. The drug development process was extremely hard, aiming to surmount complex obstacles, such as how to efficiently and safely deliver siRNAs to desired tissues and cells and how to enhance the performance of siRNAs with respect to their activity, stability, specificity and potential off-target effects. In this review, the evolution of siRNA chemical modifications and their biomedical performance are comprehensively reviewed. All clinically explored and commercialized siRNA delivery platforms, including the GalNAc (N-acetylgalactosamine)-siRNA conjugate, and their fundamental design principles are thoroughly discussed. The latest progress in siRNA therapeutic development is also summarized. This review provides a comprehensive view and roadmap for general readers working in the field.
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http://dx.doi.org/10.1038/s41392-020-0207-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305320PMC
June 2020

A self-driven bioinspired nanovehicle by leukocyte membrane-hitchhiking for early detection and treatment of atherosclerosis.

Biomaterials 2020 08 17;250:119963. Epub 2020 Apr 17.

School of Life Science, Beijing Institute of Technology, No.5 South Zhong Guan Cun Street, Beijing, 100081, China. Electronic address:

Atherosclerosis, as a silent killer, remains one of the most common causes of human morbidity and mortality worldwide due to the lack of efficient strategy for early detection and targeted therapy. In this work, a self-driven bioinspired nanovehicle is developed, which can accurately manage early atherosclerosis with simultaneously multiple-targeting, dual-modality therapy as well as noninvasive magnetic resonance imaging (MRI). The magnetic nanoclusters (MNCs) with satisfactory superparamagnetism are camouflaged with leukocyte membranes, thus acquiring inherently targeting and transmigrating capabilities to intimal foam cells in early atherosclerotic lesions, which is validated using tailor-made microfluidic devices and transwell assays. Upon sequentially embedding an anti-inflammatory drug simvastatin (ST) and decorating a targetable apolipoprotein A-I mimetic 4F peptide (AP), the as-fabricated [email protected]/AP exhibits excellent anti-atherosclerotic effects by alleviating inflammation and oxidative stress as well as promoting cholesterol efflux via RCT pathways. This bioinspired leukocyte membrane-hitchhiking strategy will open new perspectives for the future clinical translations of biocompatible nanosystem in early detection and treatment of atherosclerosis.
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http://dx.doi.org/10.1016/j.biomaterials.2020.119963DOI Listing
August 2020

A photo-triggerable aptamer nanoswitch for spatiotemporal controllable siRNA delivery.

Nanoscale 2020 May;12(20):10939-10943

Advanced Research Institute of Multidisciplinary Science; School of Life Science; Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing 100081, China.

A photo-triggerable aptamer nanoswitch was proposed for spatiotemporal regulation of siRNA delivery. Recognition between AS1411 and nucleolin was effectively blocked by a photo-labile complementary oligonucleotide, which could be reactivated with photo-irradiation, resulting in efficient tumor-targeted siRNA internalization and gene silencing in vitro and in vivo.
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http://dx.doi.org/10.1039/d0nr00301hDOI Listing
May 2020

Bioinspired exosome-like therapeutics and delivery nanoplatforms.

Authors:
Mei Lu Yuanyu Huang

Biomaterials 2020 Mar 2;242:119925. Epub 2020 Mar 2.

School of Life Science, Advanced Research Institute of Multidisciplinary Science, Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing, 100081, PR China. Electronic address:

Exosomes have emerged as appealing candidate therapeutic agents and delivery nanoplatforms due to their endogenous features and unique biological properties. However, obstacles such as low isolation yield, considerable complexity and potential safety concerns, and inefficient drug payload substantially hamper their therapeutic applicability. To this end, developing bioinspired exosome-like nanoparticles has become a promising area to overcome certain limitations of their natural counterparts. Synthetically fabrication of exosome-like nanoparticles that harbor only crucial components of exosomes through controllable protocols strongly increases the pharmaceutical acceptability of these vesicles. Assembly of exosome-like nanovesicles derived from producer cells allows for a promising strategy for scale-up production. To improve the loading capability and delivery efficiency of exosomes, hybrid exosome-like nanovesicles and membrane-camouflaged nanoparticles towards better bridging synthetic nanocarriers with natural exosomes could be designed. Building off these observations, herein, efforts are made to give an overview of bioinspired exosome-like therapeutics and delivery nanoplatforms. We briefly recapitulate the recent advance in exosome biology with focus on tailoring exosomes as therapeutics and delivery vehicles. Furthermore, we elaborately discuss the biomimicry methodologies for preparation of exosome-like nanoparticles with special emphasis on offering insights into strategies for rational design of exosome-like biomaterials as effective and safe therapeutics and delivery nanoplatforms.
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http://dx.doi.org/10.1016/j.biomaterials.2020.119925DOI Listing
March 2020

The challenge and prospect of mRNA therapeutics landscape.

Biotechnol Adv 2020 May - Jun;40:107534. Epub 2020 Feb 21.

School of Life Science, Advanced Research Institute of Multidisciplinary Science, Key Laboratory of Molecular Medicine and Biotherapy, Institute of Engineering Medicine, Beijing Institute of Technology, Beijing 100081, PR China. Electronic address:

Messenger RNA (mRNA)-based therapeutics hold the potential to cause a major revolution in the pharmaceutical industry because they can be used for precise and individualized therapy, and enable patients to produce therapeutic proteins in their own bodies without struggling with the comprehensive manufacturing issues associated with recombinant proteins. Compared with the current therapeutics, the production of mRNA is much cost-effective, faster and more flexible because it can be easily produced by in vitro transcription, and the process is independent of mRNA sequence. Moreover, mRNA vaccines allow people to develop personalized medications based on sequencing results and/or personalized conditions rapidly. Along with the great potential from bench to bedside, technical obstacles facing mRNA pharmaceuticals are also obvious. The stability, immunogenicity, translation efficiency, and delivery are all pivotal issues need to be addressed. In the recently published research results, these issues are gradually being overcome by state-of-the-art development technologies. In this review, we describe the structural properties and modification technologies of mRNA, summarize the latest advances in developing mRNA delivery systems, review the preclinical and clinical applications, and put forward our views on the prospect and challenges of developing mRNA into a new class of drug.
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http://dx.doi.org/10.1016/j.biotechadv.2020.107534DOI Listing
May 2020

Improved Nucleic Acid Therapy with Advanced Nanoscale Biotechnology.

Mol Ther Nucleic Acids 2020 Mar 17;19:581-601. Epub 2019 Dec 17.

Chinese Academy of Sciences (CAS) Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, P.R. China. Electronic address:

Due to a series of systemic and intracellular obstacles in nucleic acid (NA) therapy, including fast degradation in blood, renal clearance, poor cellular uptake, and inefficient endosomal escape, NAs may need delivery methods to transport to the cell nucleus or cytosol to be effective. Advanced nanoscale biotechnology-associated strategies, such as controlling the particle size, charge, drug loading, response to environmental signals, or other physical/chemical properties of delivery carriers, have provided great help for the in vivo and in vitro delivery of NA therapeutics. In this review, we introduce the characteristics of different NA modalities and illustrate how advanced nanoscale biotechnology assists NA therapy. The specific features and challenges of various nanocarriers in clinical and preclinical studies are summarized and discussed. With the help of advanced nanoscale biotechnology, some of the major barriers to the development of NA therapy will eventually be overcome in the near future.
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http://dx.doi.org/10.1016/j.omtn.2019.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957827PMC
March 2020

Aperture-controllable nano-electrospray emitter and its application in cardiac proteome analysis.

Talanta 2020 Jan 9;207:120340. Epub 2019 Sep 9.

Department of Chemistry and Zhongshan Hospital, Fudan University, Shanghai, 200433, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.

The emitter clogging is the most common hardware failure of nano-electrospray ionization, to improve the durability and electrospray stability of fused silica emitters, we demonstrate a means of fabricating nano-electrospray emitters with controllable aperture size and gradually-narrowed channel on the tip. We simulated the fluid morphologies in the emitter channels by computational fluid dynamics and found more stable flow on aperture-controllable nano-electrospray emitter. Besides, we found the unstable flow sections of commercial emitters match the actual clogging sections very well, indicating the main cause of emitter clogging is unstable flow. We further tested the emitters by nano-LC-MS based proteome analysis. Compared with the commercial emitter, aperture-controllable nano-electrospray emitters promoted the total ion chromatogram intensity by 25%, the number of identified proteins by 6.58%, and the number of identified peptides by 7.87%. In total, 989 proteins were identified from 1 μg of extracted mouse cardiac proteins. After the optimization by using mouse samples, we analyzed clinical auricular dextral tissues from patients undergoing cardiac surgery and found 16 proteins related to atrial fibrillation. Overall, aperture-controllable nano-electrospray emitter exhibits better sensitivity and reproducibility in the application of nano-LC-MS cardiac proteome analysis.
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http://dx.doi.org/10.1016/j.talanta.2019.120340DOI Listing
January 2020

Transdermal Delivery of Nucleic Acid Mediated by Punching and Electroporation.

Methods Mol Biol 2020 ;2050:101-112

National Key Laboratory of Science and Technology on Micro/Nano Fabrication, Institute of Microelectronics, Peking University, Beijing, China.

Transdermal delivery of gene medicine holds a great promise in gene therapy, and electroporation-mediated method is a high-efficiency drug transfer technique. Traditional skin electroporation approaches require high voltage that may cause severe injure. In this chapter, we provide a detailed protocol of a novel skin electroporation approach via combination of a microneedle roller and a flexible interdigitated electroporation array (FIEA) for efficient delivery of DNA and siRNA into mouse skin. This electroporation protocol assisted by punching with the microneedle roller represents significant advantages over treatment with electroporation alone, allowing successful nucleic acid transportation at low voltage, with ideal safety outcomes. We describe the details of fabrication process of the FIEA, experiment preparation, and mouse thigh skin electroporation.
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http://dx.doi.org/10.1007/978-1-4939-9740-4_11DOI Listing
October 2020

Clinical advances of siRNA therapeutics.

J Gene Med 2019 07 17;21(7):e3097. Epub 2019 Jun 17.

School of Life Science, Advanced Research Institute of Multidisciplinary Science, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing, 100081, P. R. China.

Small interfering RNA (siRNA) enables efficient target gene silencing by employing a RNA interference (RNAi) mechanism, which can compromise gene expression and regulate gene activity by cleaving mRNA or repressing its translation. Twenty years after the discovery of RNAi in 1998, ONPATTRO™ (patisiran) (Alnylam Pharmaceuticals, Inc.), a lipid formulated siRNA modality, was approved for the first time by United States Food and Drug Administration and the European Commission in 2018. With this milestone achievement, siRNA therapeutics will soar in the coming years. Here, we review the discovery and the mechanisms of RNAi, briefly describe the delivery technologies of siRNA, and summarize recent clinical advances of siRNA therapeutics.
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http://dx.doi.org/10.1002/jgm.3097DOI Listing
July 2019

RNAi therapeutic and its innovative biotechnological evolution.

Biotechnol Adv 2019 Sep - Oct;37(5):801-825. Epub 2019 Apr 26.

Advanced Research Institute of Multidisciplinary Science, School of Life Science, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing 100081, PR China. Electronic address:

Recently, United States Food and Drug Administration (FDA) and European Commission (EC) approved Alnylam Pharmaceuticals' RNA interference (RNAi) therapeutic, ONPATTRO™ (Patisiran), for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. This is the first RNAi therapeutic all over the world, as well as the first FDA-approved treatment for this indication. As a milestone event in RNAi pharmaceutical industry, it means, for the first time, people have broken through all development processes for RNAi drugs from research to clinic. With this achievement, RNAi approval may soar in the coming years. In this paper, we introduce the basic information of ONPATTRO and the properties of RNAi and nucleic acid therapeutics, update the clinical and preclinical development activities, review its complicated development history, summarize the key technologies of RNAi at early stage, and discuss the latest advances in delivery and modification technologies. It provides a comprehensive view and biotechnological insights of RNAi therapy for the broader audiences.
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http://dx.doi.org/10.1016/j.biotechadv.2019.04.012DOI Listing
February 2020

Self-assembling supramolecular dendrimer nanosystem for PET imaging of tumors.

Proc Natl Acad Sci U S A 2018 11 22;115(45):11454-11459. Epub 2018 Oct 22.

Aix-Marseille University, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Equipe Labellisée Ligue Contre le Cancer, 13288 Marseille, France;

Bioimaging plays an important role in cancer diagnosis and treatment. However, imaging sensitivity and specificity still constitute key challenges. Nanotechnology-based imaging is particularly promising for overcoming these limitations because nanosized imaging agents can specifically home in on tumors via the "enhanced permeation and retention" (EPR) effect, thus resulting in enhanced imaging sensitivity and specificity. Here, we report an original nanosystem for positron emission tomography (PET) imaging based on an amphiphilic dendrimer, which bears multiple PET reporting units at the terminals. This dendrimer is able to self-assemble into small and uniform nanomicelles, which accumulate in tumors for effective PET imaging. Benefiting from the combined dendrimeric multivalence and EPR-mediated passive tumor targeting, this nanosystem demonstrates superior imaging sensitivity and specificity, with up to 14-fold increased PET signal ratios compared with the clinical gold reference 2-fluorodeoxyglucose ([F]FDG). Most importantly, this dendrimer system can detect imaging-refractory low-glucose-uptake tumors that are otherwise undetectable using [F]FDG. In addition, it is endowed with an excellent safety profile and favorable pharmacokinetics for PET imaging. Consequently, this dendrimer nanosystem constitutes an effective and promising approach for cancer imaging. Our study also demonstrates that nanotechnology based on self-assembling dendrimers provides a fresh perspective for biomedical imaging and cancer diagnosis.
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http://dx.doi.org/10.1073/pnas.1812938115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233080PMC
November 2018

A Dual Targeting Dendrimer-Mediated siRNA Delivery System for Effective Gene Silencing in Cancer Therapy.

J Am Chem Soc 2018 11 1;140(47):16264-16274. Epub 2018 Nov 1.

Aix-Marseille Université , CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, "Equipe Labellisée Ligue Contre le Cancer", 13288 Marseille , France.

Small interfering RNA (siRNA) is emerging as a novel therapeutic for treating various diseases, provided a safe and efficient delivery is available. In particular, specific delivery to target cells is critical for achieving high therapeutic efficacy while reducing toxicity. Amphiphilic dendrimers are emerging as novel promising carriers for siRNA delivery by virtue of the combined multivalent cooperativity of dendrimers with the self-assembling property of lipid vectors. Here, we report a ballistic approach for targeted siRNA delivery to cancer cells using an amphiphilic dendrimer equipped with a dual targeting peptide bearing an RGDK warhead. According to the molecular design, the amphiphilic dendrimer was expected to deliver siRNA effectively, while the aim of the targeting peptide was to home in on tumors via interaction of its warhead with integrin and the neuropilin-1 receptor on cancer cells. Coating the positively charged siRNA/dendrimer delivery complex with the negatively charged segment of the targeting peptide via electrostatic interactions led to small and stable nanoparticles which were able to protect siRNA from degradation while maintaining the accessibility of RGDK for targeting cancer cells and preserving the ability of the siRNA to escape from endosomes. The targeted system had enhanced siRNA delivery, stronger gene silencing, and more potent anticancer activity compared to nontargeted or covalent dendrimer-based systems. In addition, neither acute toxicity nor induced inflammation was observed. Consequently, this delivery system constitutes a promising nonviral vector for targeted delivery and can be further developed to provide RNAi-based personalized medicine against cancer. Our study also gives new perspectives on the use of nanotechnology based on self-assembling dendrimers in various biomedical applications.
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http://dx.doi.org/10.1021/jacs.8b10021DOI Listing
November 2018

Continuous Vector-free Gene Transfer with a Novel Microfluidic Chip and Nanoneedle Array.

Curr Drug Deliv 2019 ;16(2):164-170

Advanced Research Institute of Multidisciplinary Science, School of Life Science, Key Laboratory of Molecular Medicine and Biotheranotics, Ministry of Industry and Information Technology, Beijing Institute of Technology, Beijing, 100081, China.

Background: Delivery of foreign cargoes into cells is of great value for bioengineering research and therapeutic applications.

Objective: In this study, we proposed and established a carrier-free gene delivery platform utilizing staggered herringbone channel and silicon nanoneedle array, to achieve high-throughput in vitro gene transfection.

Methods: With this microchip, fluidic micro vortices could be induced by the staggered-herringboneshaped grooves within the channel, which increased the contact frequency of the cells with the channel substrate. Transient disruptions on the cell membrane were well established by the nanoneedle array on the substrate.

Result: Compared to the conventional nanoneedle-based delivery system, proposed microfluidic chip achieved flow-through treatment with high gene transfection efficiency (higher than 20%) and ideal cell viability (higher than 95%).

Conclusion: It provides a continuous processing environment that can satisfy the transfection requirement of large amounts of biological molecules, showing high potential and promising prospect for both basic research and clinical application.
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http://dx.doi.org/10.2174/1567201815666181017095044DOI Listing
April 2019

Fluorinated Oligoethylenimine Nanoassemblies for Efficient siRNA-Mediated Gene Silencing in Serum-Containing Media by Effective Endosomal Escape.

Nano Lett 2018 10 27;18(10):6301-6311. Epub 2018 Sep 27.

Chinese Academy of Sciences (CAS) Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience , National Center for Nanoscience and Technology of China , Beijing 100190 , P. R. China.

Efficient small interfering RNA (siRNA) delivery in the presence of serum is of crucial importance for effective gene therapy. Fluorinated vectors are considered to be attractive candidates for siRNA-mediated gene therapy because of their delivery efficacy in serum-containing media. However, the mechanisms driving the superior gene transfection behavior of fluorinated vectors are still not well-understood, and comprehensive investigations are warranted. Herein, we fabricated a library of perfluorooctanoyl fluoride-fluorinated (PFF-fluorinated) oligoethylenimines (f OEIs, x is the PFF:OEI feeding ratio), which can readily form nanoassemblies (f OEI NAs) capable of efficient siRNA delivery in cells cultured in medium both devoid of and supplemented with fetal bovine serum (FBS). The gene silencing test in serum-containing medium revealed that the fOEI/siRNA NAs achieved a luciferase silencing of ∼88.4% in Luc-HeLa cells cultured in FBS-containing medium, which was almost 2-fold greater than the silencing efficacy of siRNA delivered by the commercially available vector Lipo 2000 (∼48.8%). High levels of apolipoprotein B silencing were also achieved by fOEI/siRNA NAs in vivo. For an assessment of the underlying mechanisms of the efficacy of gene silencing of fluorinated vectors, two alkylated OEIs, aOEI-C8 and aOEI-C12, were fabricated as controls with similar molecular structure and hydrophobicity to that of fOEI, respectively. In vitro investigations showed that the superior gene delivery exhibited by fOEI NAs derived from the potent endosomal disruption capability of fluorinated vectors in the presence of serum, which was essentially attributed to the serum protein adsorption resistance of the fOEI NAs. Therefore, this work provides an innovative approach to siRNA delivery as well as insights into fluorine-associated serum resistance.
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http://dx.doi.org/10.1021/acs.nanolett.8b02553DOI Listing
October 2018

siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin.

Mol Ther Nucleic Acids 2018 Sep 8;12:805-816. Epub 2018 Aug 8.

Advanced Research Institute of Multidisciplinary Science and School of Life Science, Beijing Institute of Technology, Beijing 100081, China. Electronic address:

Pancreatic cancer is currently one of the deadliest of the solid malignancies, whose incidence and death rates are increasing consistently during the past 30 years. Ribonucleotide reductase (RR) is a rate-limiting enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides, which are essential for DNA synthesis and replication. In this study, 23 small interfering RNAs (siRNAs) against RRM2, the second subunit of RR, were designed and screened, and one of them (termed siRRM2), with high potency and good RNase-resistant capability, was selected. Transfection of siRRM2 into PANC-1, a pancreatic cell line, dramatically repressed the formation of cell colonies by inducing remarkable cell-cycle arrest at S-phase. When combining with doxorubicin (DOX), siRRM2 improved the efficacy 4 times more than applying DOX alone, suggesting a synergistic effect of siRRM2 and DOX. Moreover, the combined application of siRRM2-loaded lipid nanoparticle and DOX significantly suppressed the tumor growth on the PANC-1 xenografted murine model. The inhibition efficiency revealed by tumor weight at the endpoint of the treatment reached more than 40%. Hence, siRRM2 effectively suppressed pancreatic tumor growth alone or synergistically with DOX. This study provides a feasible target gene, a drug-viable siRNA, and a promising therapeutic potential for the treatment of pancreatic cancer.
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http://dx.doi.org/10.1016/j.omtn.2018.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118156PMC
September 2018
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