Enzyme-Catalyzed One-Step Synthesis of Ionizable Cationic Lipids for Lipid Nanoparticle-Based mRNA COVID-19 Vaccines.

Ionizable cationic lipid-containing lipid nanoparticles (LNPs) are the most clinically advanced non-viral gene delivery platforms, holding great potential for gene therapeutics. This is exemplified by the two COVID-19 vaccines employing mRNA-LNP technology from Pfizer/BioNTech and Moderna. Herein, we develop a chemical library of ionizable cationic lipids through a one-step chemical-biological enzyme-catalyzed esterification method, and the synthesized ionizable lipids were further prepared to be LNPs for mRNA delivery. Through orthogonal design of experiment methodology screening, the top-performing AA3-DLin LNPs show outstanding mRNA delivery efficacy and long-term storage capability. Furthermore, the AA3-DLin LNP COVID-19 vaccines encapsulating SARS-CoV-2 spike mRNAs successfully induced strong immunogenicity in a BALB/c mouse model demonstrated by the antibody titers, virus challenge, and T cell immune response studies. The developed AA3-DLin LNPs are an excellent mRNA delivery platform, and this study provides an overall perspective of the ionizable cationic lipids, from aspects of lipid design, synthesis, screening, optimization, fabrication, characterization, and application.

Lipid-Polymer Hybrid "Particle-in-Particle" Nanostructure Gene Delivery Platform Explored for Lyophilizable DNA and mRNA COVID-19 Vaccines.

SARS-CoV-2 has led to a worldwide pandemic, catastrophically impacting public health and the global economy. Herein, a new class of lipid-modified polymer poly (ß-amino esters) (L-PBAEs) is developed via enzyme-catalyzed esterification and further formulation of the L-PBAEs with poly(d,l-lactide-coglycolide)-b-poly(ethylene glycol) (PLGA-PEG) leads to self-assembly into a "particle-in-particle" (PNP) nanostructure for gene delivery. Out of 24 PNP candidates, the top-performing PNP/C12-PBAE nanoparticles efficiently deliver both DNA and mRNA in vitro and in vivo, presenting enhanced transfection efficacy, sustained gene release behavior, and excellent stability for at least 12 months of storage at -20 °C after lyophilization without loss of transfection efficacy. Encapsulated with spike encoded plasmid DNA and mRNA, the lipid-modified polymeric PNP COVID-19 vaccines successfully elicit spike-specific antibodies and Th1-biased T cell immune responses in immunized mice even after 12 months of lyophilized storage at -20 °C. This newly developed lipid-polymer hybrid PNP nanoparticle system demonstrates a new strategy for both plasmid DNA and mRNA delivery with the capability of long-term lyophilized storage.

COVID-19 Pandemic Impact on Cardiometabolic Markers in Adults in Chongqing, China: A Retrospective Cohort Study.

The influx of COVID-19 infection and government-enforced lockdowns and social isolation changed people's lifestyles. Concerns regarding the health impact of the COVID-19 pandemic due to the new sedentary lifestyle. This study aims to investigate the impact of the COVID-19 pandemic on cardiovascular health factors. A retrospective observational study was conducted using historical medical records. The cohort consisted of healthy adults (without chronic non-communicable diseases) over 18 years of age who have undertaken a health examination at the Chongqing Medical University from 2019 to 2020. The analysis of covariance (ANCOVA) test was used to compare variables between 2019 and 2020. The effect of exposure time to COVID-19 on cardiometabolic markers was analyzed using multiple linear regression models. 29,773 participants took part in this study. The average age was 42.5 ± 13.44 years at baseline, and the average follow-up period was 12.7 ± 2.8 months. Analysis showed that weight, BMI, waist circumference, hip circumference, WHR, fasting blood glucose, TG, LDL, uric acid, and liver enzymes increased significantly during the COVID-19 pandemic (P < 0.05). This study showed evidence that the COVID-19 pandemic and its control measures negatively impacted cardiometabolic profiles.

Next-Generation Vaccines: Nanoparticle-Mediated DNA and mRNA Delivery.

Nucleic acid vaccines are a method of immunization aiming to elicit immune responses akin to live attenuated vaccines. In this method, DNA or messenger RNA (mRNA) sequences are delivered to the body to generate proteins, which mimic disease antigens to stimulate the immune response. Advantages of nucleic acid vaccines include stimulation of both cell-mediated and humoral immunity, ease of design, rapid adaptability to changing pathogen strains, and customizable multiantigen vaccines. To combat the SARS-CoV-2 pandemic, and many other diseases, nucleic acid vaccines appear to be a promising method. However, aid is needed in delivering the fragile DNA/mRNA payload. Many delivery strategies have been developed to elicit effective immune stimulation, yet no nucleic acid vaccine has been FDA-approved for human use. Nanoparticles (NPs) are one of the top candidates to mediate successful DNA/mRNA vaccine delivery due to their unique properties, including unlimited possibilities for formulations, protective capacity, simultaneous loading, and delivery potential of multiple DNA/mRNA vaccines. This review will summarize the many varieties of novel NP formulations for DNA and mRNA vaccine delivery as well as give the reader a brief synopsis of NP vaccine clinical trials. Finally, the future perspectives and challenges for NP-mediated nucleic acid vaccines will be explored.