Design Rules for the Nano‐Bio Interface of Nanodiamonds: Implications for siRNA Vectorization

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Abstract

The enormous therapeutic potential of selective ribonucleic acid (RNA) interference has recently been manifested by the approval of several small interfering RNA (siRNA)‐based drugs. However, the efficacy of siRNA delivery is still limited, and an extensive search for alternative and highly effective delivery approaches is ongoing. With this aim, three generations of non‐viral vectors based on modified nanodiamonds (NDs) have been gradually developed in the past decade. They show great promise due to the negligible toxicity of the ND core. Here, a robust methodological approach is presented to enable the evaluation of new vector nanomaterials. Using a new type of third‐generation ND vector coated with a copolymer with tunable charge density, variables such as colloidal stability, surface electrostatic properties, the molecular composition of the copolymer, and the mode of complexation with siRNA are optimized. Using an innovative data processing strategy, the results are related to biological potency, toxicity, and cell proliferation. Finally, the optimized composition of a coating copolymer consisting of a cationic component, 2‐dimethylaminoethyl methacrylate, and an electroneutral biocompatible component, N‐(2‐hydroxypropyl) methacrylamide, is evaluated. The optimized NDs vectors are colloidally and biologically stable siRNA delivery tools with broad potential for RNA interference‐based therapeutics.

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Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Lindsey Baden, Hana El Sahly, Brandon Essink … (2020)

Abstract Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. Conclusions The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)