Quantitative analysis of mRNA-lipid nanoparticle stability in human plasma and serum by size-exclusion chromatography coupled with dual-angle light scattering.

Understanding the stability of mRNA loaded lipid nanoparticles (mRNA-LNPs) is imperative for their clinical development. Herein, we propose the use of size-exclusion chromatography coupled with dual-angle light scattering (SEC-MALS) as a new approach to assessing mRNA-LNP stability in pure human serum and plasma. By applying a dual-column configuration to attenuate interference from plasma components, SEC-MALS was able to elucidate the degradation kinetics and physical property changes of mRNA-LNPs, which have not been observed accurately by conventional dynamic light scattering techniques.

Guanidinium-Perfunctionalized Polyhedral Oligomeric Silsesquioxanes as Highly Potent Antimicrobials against Planktonic Microbes, Biofilms, and Coronavirus.

Supramolecules have been drawing increasing attention recently in addressing healthcare challenges caused by infectious pathogens. We herein report a novel class of guanidinium-perfunctionalized polyhedral oligomeric silsesquioxane (Gua-POSS) supramolecules with highly potent antimicrobial activities. The modular structure of Gua-POSS consists of an inorganic T10 or T8 core ( = 10 or 8), flexible linear linkers of varying lengths ( = 1 or 3), and peripherally aligned cationic guanidinium groups as the membrane-binding units.

Deciphering Nanoparticle Trafficking into Glioblastomas Uncovers an Augmented Antitumor Effect of Metronomic Chemotherapy.

Nanoparticles have been explored in glioblastomas as they can traverse the blood-brain barrier and target glioblastoma selectively. However, direct observation of nanoparticle trafficking into glioblastoma cells and their underlying intracellular fate after systemic administration remains uncharacterized. Here, based on high-resolution transmission electron microscopy experiments of an intracranial glioblastoma model, it is shown that ligand-modified nanoparticles can traverse the blood-brain barrier, endocytose into the lysosomes of glioblastoma cells, and undergo endolysosomal escape upon photochemical ionization.

A chemical biology approach reveals a dependency of glioblastoma on biotin distribution.

Glioblastoma (GBM) is a uniformly lethal disease driven by glioma stem cells (GSCs). Here, we use a chemical biology approach to unveil previously unknown GBM dependencies. By studying sulconazole (SN) with anti-GSC properties, we find that SN disrupts biotin distribution to the carboxylases and histones.

Emerging strategies in developing multifunctional nanomaterials for cancer nanotheranostics.

Cancer involves a collection of diseases with a common trait - dysregulation in cell proliferation. At present, traditional therapeutic strategies against cancer have limitations in tackling various tumors in clinical settings. These include chemotherapeutic resistance and the inability to overcome intrinsic physiological barriers to drug delivery.

Continuous-wave near-infrared stimulated-emission depletion microscopy using downshifting lanthanide nanoparticles.

Stimulated-emission depletion (STED) microscopy has profoundly extended our horizons to the subcellular level. However, it remains challenging to perform hours-long, autofluorescence-free super-resolution imaging in near-infrared (NIR) optical windows under facile continuous-wave laser depletion at low power. Here we report downshifting lanthanide nanoparticles that enable background-suppressed STED imaging in all-NIR spectral bands (λ = 808 nm, λ = 1,064 nm and λ = 850-900 nm), with a lateral resolution of below 20 nm and zero photobleaching.

Combating the Coronavirus Pandemic: Early Detection, Medical Treatment, and a Concerted Effort by the Global Community.

The World Health Organization (WHO) has declared the outbreak of 2019 novel coronavirus, known as 2019-nCoV, a pandemic, as the coronavirus has now infected over 2.6 million people globally and caused more than 185,000 fatalities as of April 23, 2020. Coronavirus disease 2019 (COVID-19) causes a respiratory illness with symptoms such as dry cough, fever, sudden loss of smell, and, in more severe cases, difficulty breathing.

Antiviral activities of peptide-based covalent inhibitors of the Enterovirus 71 3C protease.

Hand, Foot and Mouth Disease is a highly contagious disease caused by a range of human enteroviruses. Outbreaks occur regularly, especially in the Asia-Pacific region, putting a burden on public healthcare systems. Currently, there is no antiviral for treating this infectious disease and the only vaccines are limited to circulation in China, presenting an unmet medical need that needs to be filled urgently.

Antiviral activities of 15 dengue NS2B-NS3 protease inhibitors using a human cell-based viral quantification assay.

The dengue virus is a mosquito-borne pathogen responsible for an estimated 50-100 million human dengue infections annually. There are currently no approved drugs against this disease, resulting in a major unmet clinical need. The dengue viral NS2B-NS3 protease has been identified as a plausible drug target due to its involvement in viral replication in mammalian host cells.

A P2 and P3 substrate specificity comparison between the Murray Valley encephalitis and West Nile virus NS2B/NS3 protease using C-terminal agmatine dipeptides.

The Murray Valley encephalitis virus (MVEV) and the West Nile virus (WNV) are mosquito-borne single-stranded RNA Flaviviruses responsible for many cases of viral encephalitis and deaths worldwide. The former is endemic in north Australia and Papua New Guinea while the latter has spread to different parts of the world and was responsible for a recent North American outbreak in 2012, resulting in 243 fatalities. There is currently no approved vaccines or drugs against MVEV and WNV viral infections.

Substrate-based peptidomimetic inhibitors of the Murray Valley encephalitis virus NS2B/NS3 serine protease: a P1-P4 SAR study.

Murray Valley encephalitis is an infectious disease spread by a mosquito-borne virus endemic in Papua New Guinea and northern Australia. In the past decade, it has spread to various regions of Australia and there is currently no therapeutic treatment against this disease. An attractive drug target is the viral serine protease NS2B/NS3, a critical enzyme involved in viral replication.

Electroenhanced solid-phase microextraction of methamphetamine with commercial fibers.

Electroenhanced solid-phase microextraction (EE-SPME) method with gas chromatographic mass spectrometric analysis was investigated for the determination of methamphetamine in urine sample with commercial fibers. In this approach, commercial SPME fibers were used in direct immersion mode with an applied potential to extract methamphetamine. EE-SPME was more effective in the extraction compared to conventional SPME (i.

NMR analysis of a novel enzymatically active unlinked dengue NS2B-NS3 protease complex.

The dengue virus (DENV) is a mosquito-borne pathogen responsible for an estimated 100 million human infections annually. The viral genome encodes a two-component trypsin-like protease that contains the cofactor region from the nonstructural protein NS2B and the protease domain from NS3 (NS3pro). The NS2B-NS3pro complex plays a crucial role in viral maturation and has been identified as a potential drug target.

Novel agmatine dipeptide inhibitors against the West Nile virus NS2B/NS3 protease: a P3 and N-cap optimization study.

This communication describes the synthesis and inhibitory activities of thirty-seven novel C-terminal agmatine dipeptides used as screening compounds to study the structure-activity relationship between active-site peptidomimetics and the West Nile virus (WNV) NS2B/NS3 serine protease. Our efforts lead to the discovery of a novel agmatine dipeptide inhibitor (compound 33, IC50 2.6 ± 0.