A Chemoinformatic-Guided Synthesis of a Spleen-Expressing mRNA Lipid Nanoparticle Platform.

mRNA lipid nanoparticles (LNPs) are a powerful technology that are actively being investigated for their ability to prevent, treat, and study disease. However, a major limitation remains: achieving extrahepatic mRNA expression. The development of new carriers could enable the expression of mRNA in non-liver targets, thus expanding the utility of mRNA-based medicines.

Effects of coagulation pre-treatment on chemical and microbial properties of water-soil-plant systems of constructed wetlands.

Chemical coagulation has gained recognition as an effective technique to enhance the removal efficiency of pollutants in wastewater prior to their entry into a constructed wetland (CW) system. However, its potential impact on the chemical and microbial properties of soil and plant systems within CWs requires further research. This study investigated the impact of using ferric chloride (FeCl) as a pre-treatment stage for dairy wastewater (DWW) on the chemical and microbial properties of water-soil-plant systems of replicated pilot-scale CWs, comparing them to CWs treating untreated DWW.

A Lung-Expressing mRNA Delivery Platform with Tunable Activity in Hypoxic Environments.

Messenger RNA (mRNA) delivery platforms often facilitate protein expression in the liver following intravenous injection and have been optimized for use in normally oxygenated cells (21% O atmosphere). However, there is a growing need for mRNA therapy in diseases affecting non-liver organs, such as the lungs. Additionally, many diseases are characterized by hypoxia (<21% O atmosphere), a state of abnormally low oxygenation in cells and tissues that can reduce the efficacy of mRNA therapies by upwards of 80%.

Polymeric cGAMP microparticles affect the immunogenicity of a broadly active influenza mRNA lipid nanoparticle vaccine.

Influenza outbreaks are a major burden worldwide annually. While seasonal vaccines do provide protection against infection, they are limited in that they need to be updated every year to account for the constantly mutating virus. Recently, lipid nanoparticles (LNPs) encapsulating mRNA have seen major success as a vaccine platform for SARS-CoV-2.

Regioselective Palladium-Catalyzed Chain-Growth Allylic Amination Polymerization of Vinyl Aziridines.

Organometallic-mediated chain growth polymerization of readily accessible chemical building blocks is responsible for important commercial and technological advances in polymer science, but the incorporation of heteroatoms into the polymer backbone through these mechanisms remains a challenge. Transition metal π-allyl complexes are well-developed organometallic intermediates for carbon-heteroatom bond formation in small-molecule catalysis yet remain underexplored in polymer science. Here, we developed a regioselective palladium-phosphoramidite-catalyzed chain-growth allylic amination polymerization of vinyl aziridines for the synthesis of novel nitrogen-rich polymers via ambiphilic π-allyl complexes.

Polyphenolic Nanoparticle Platforms (PARCELs) for and mRNA Delivery.

Despite their successful implementation in the COVID-19 vaccines, lipid nanoparticles (LNPs) still face a central limitation in the delivery of mRNA payloads: endosomal trapping. Improving upon this inefficiency could afford improved drug delivery systems, paving the way toward safer and more effective mRNA-based medicines. Here, we present olyphenolic nnopatil patforms (PARCELs) as effective mRNA delivery systems.

Advances in non-viral mRNA delivery to the spleen.

Developing safe and effective delivery strategies for localizing messenger RNA (mRNA) payloads to the spleen is an important goal in the field of genetic medicine. Accomplishing this goal is challenging due to the instability, size, and charge of mRNA payloads. Here, we provide an analysis of non-viral delivery technologies that have been developed to deliver mRNA payloads to the spleen.

Intracellular proteomics and extracellular vesiculomics as a metric of disease recapitulation in 3D-bioprinted aortic valve arrays.

In calcific aortic valve disease (CAVD), mechanosensitive valvular cells respond to fibrosis- and calcification-induced tissue stiffening, further driving pathophysiology. No pharmacotherapeutics are available to treat CAVD because of the paucity of (i) appropriate experimental models that recapitulate this complex environment and (ii) benchmarking novel engineered aortic valve (AV)-model performance. We established a biomaterial-based CAVD model mimicking the biomechanics of the human AV disease-prone fibrosa layer, three-dimensional (3D)-bioprinted into 96-well arrays.

Understanding phosphorus mobilization mechanisms in acidic soil amended with calcium-silicon-magnesium-potassium fertilizer.

Calcium-silicon-magnesium-potassium fertilizer (CSMP) is usually used as an amendment to counteract soil acidification caused by historical excessive nitrogen (N) applications. However, the impact of CSMP addition on phosphorus (P) mobilization in acidic soils and the related mechanisms are not fully understood. Specifically, a knowledge gap exists with regards to changes in soil extracellular enzymes that contribute to P release.

Enhancing the Functionality of Immunoisolated Human SC-βeta Cell Clusters through Prior Resizing.

The transplantation of immunoisolated stem cell derived beta cell clusters (SC-β) has the potential to restore physiological glycemic control in patients with type I diabetes. This strategy is attractive as it uses a renewable β-cell source without the need for systemic immune suppression. SC-β cells have been shown to reverse diabetes in immune compromised mice when transplanted as ≈300 µm diameter clusters into sites where they can become revascularized.

Messenger RNA Therapy for Female Reproductive Health.

Female reproductive health has traditionally been an underrepresented area of research in the drug delivery sciences. This disparity is also seen in the emerging field of mRNA therapeutics, a class of medicines that promises to treat and prevent disease by upregulating protein expression in the body. Here, we review advances in mRNA therapies through the lens of improving female reproductive health.

Nanoparticle-Mediated Delivery of Anti-PU.1 siRNA via Localized Intracisternal Administration Reduces Neuroinflammation.

Neuroinflammation is a hallmark of neurodegenerative disorders including Alzheimer's disease (AD). Microglia, the brain's immune cells, express many of the AD-risk loci identified in genome wide association studies and present a promising target for anti-inflammatory RNA therapeutics but are difficult to transfect with current methods. Here, several lipid nanoparticle (LNP) formulations are examined, and a lead candidate that supports efficient RNA delivery in cultures of human stem cell-derived microglia-like cells (iMGLs) and animal models of neuroinflammation is identified.

Advances in Nonviral mRNA Delivery Materials and Their Application as Vaccines for Melanoma Therapy.

Messenger RNA (mRNA) vaccines are promising platforms for cancer immunotherapy because of their potential to encode for a variety of tumor antigens, high tolerability, and capacity to induce strong antitumor immune responses. However, the clinical translation of mRNA cancer vaccines can be hindered by the inefficient delivery of mRNA . In this review, we provide an overview of mRNA cancer vaccines by discussing their utility in treating melanoma.

A Unified Strategy to Improve Lipid Nanoparticle Mediated mRNA Delivery Using Adenosine Triphosphate.

A central goal of chemical and drug delivery sciences is to maximize the therapeutic efficacy of a given drug at the lowest possible dose. Here, we report a generalizable strategy that can be utilized to improve the delivery of mRNA drugs using lipid nanoparticles (LNPs), the clinically approved chemistry platforms utilized in the Moderna and Pfizer/BioNTech COVID-19 vaccines. In brief, our strategy updates the chemistry of LNPs to incorporate adenosine triphosphate (ATP) alongside mRNA, a modification that results in upward of a 79-fold increase in LNP-delivered mRNA-encoded protein expression and a 24-fold increase when compared to parent mRNA LNP formulations that do not contain ATP.

Engineering nanoparticle toolkits for mRNA delivery.

The concept of using mRNA to produce its own medicine in situ in the body makes it an ideal drug candidate, holding great potential to revolutionize the way we approach medicine. The unique characteristics of mRNA, as well as its customizable biomedical functions, call for the rational design of delivery systems to protect and transport mRNA molecules. In this review, a nanoparticle toolkit is presented for the development of mRNA-based therapeutics from a drug delivery perspective.

Ongoing Clinical Trials of Nonviral siRNA Therapeutics.

Short interfering RNAs (siRNA) are a powerful class of genetic medicines whose clinical translation can be hindered by their suboptimal delivery properties . Here, we provide a clinically focused overview that summarizes ongoing siRNA clinical trials from the perspective of innovations in nonviral delivery strategies. More specifically, our review begins by highlighting the delivery barriers and physiochemical properties of siRNA that make it challenging to deliver it .

Drainage status of grassland peat soils in Ireland: Extent, efficacy and implications for GHG emissions and rewetting efforts.

Peatlands have been artificially drained and degraded over 100s of years and have released huge amounts of carbon dioxide (CO) as a result. In organic grassland soils, raising the water table to prevent such emissions is being proposed to meet national greenhouse gas emission targets for the land use sector. At present, all of these soils (335,000 ha) are assumed to be drained (as no information has been available on their drainage status) within national emission inventory reporting and are therefore responsible for significant emissions (8-9 million tonnes CO-equivalent annually).

An Efficacy and Mechanism Driven Study on the Impact of Hypoxia on Lipid Nanoparticle Mediated mRNA Delivery.

Hypoxia is a common hallmark of human disease that is characterized by abnormally low oxygen levels in the body. While the effects of hypoxia on many small molecule-based drugs are known, its effects on several classes of next-generation medications including messenger RNA therapies warrant further study. Here, we provide an efficacy- and mechanism-driven study that details how hypoxia impacts the cellular response to mRNA therapies delivered using 4 different chemistries of lipid nanoparticles (LNPs, the frontrunner class of drug delivery vehicles for translational mRNA therapy utilized in the Moderna and Pfizer/BioNTech COVID-19 vaccines).

Effects of wastewater pre-treatment on clogging of an intermittent sand filter.

Intermittent sand filters (ISFs) are widely used in rural areas to treat domestic and dilute agricultural wastewater due to their simplicity, efficacy and relative low cost. However, filter clogging reduces their operational lifetime and sustainability. To reduce the potential of filter clogging, this study examined pre-treatment of dairy wastewater (DWW) by coagulation with ferric chloride (FeCl) prior to treatment in replicated, pilot-scale ISFs.

Phosphorus and iron-oxide transport from a hydrologically isolated grassland hillslope.

Dissolved reactive phosphorus (DRP) loss from agricultural soils can negatively affect water quality. Shallow subsurface pathways can dominate P losses in grassland soils, especially in wetter months when waterlogging is common. This study investigated the processes controlling intra- and inter-event and seasonal DRP losses from poorly drained permanent grassland hillslope plots.

A Call to Action to Address the Burden of Cardiovascular Disease in People with Diabetes.

In 2022, the Global Heart Hub held a Cardio-Diabetes Think Tank to develop consensus on actions that need to be taken to address the growing burden of diabetes and cardiovascular disease (CVD). Across the world, diabetes affects almost half a billion people, who have a twofold increased risk of CVD. The patient-led think tank brought together the diabetes and CVD communities, with representatives from leading global and regional patient and professional organisations, and produced a report outlining tangible and specific actions that reflect what matters most to patients.

Factors controlling shallow subsurface dissolved reactive phosphorus concentration and loss kinetics from poorly drained saturated grassland soils.

Shallow subsurface pathways dominate dissolved reactive phosphorus (DRP) losses in grassland soils that are: poorly drained, shallow, or have a perched water table in wetter months causing saturation-excess runoff. Saturated conditions can lead to anoxia, which can accelerate phosphorus (P) loss. Two scales of investigation were utilized in this study.