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The bleeding disorder hemophilia A (HemA) requires systemic functional factor VIII protein infusions on prophylactic schedules. Recently, chemically modified mRNAs have emerged as promising protein replacement therapies to reduce repeated infusions and improve safety profiles. However, the influence of base modifications on mRNA translation kinetics to specific cell types remains unexplored. In this study, towards developing mRNA therapeutics for haemophilia A, we synthesized chemically modified mRNAs with commercially available base modifications of adenine, guanine, uridine, and cytidine, and evaluated in vitro transcription yield and translation kinetics in hepatic cell lines using reporter eGFP mRNA. Our findings demonstrated that mRNA with N 1 -methyl pseudouridine (m 1 Ψ) showed a 5-12-fold increase in translation efficiency in both hepatic and endothelial cell lines. As a proof of concept for developing mRNA therapy for HemA, where FVIII is deficient, we developed a m 1 Ψ modified functional FVIII mRNA with our liver-targeting lipid nanoparticle (Gal-LNP) system. We evaluated its delivery efficiencies in both hepatic cell lines and the HemA mouse model. The m 1 Ψ-FVIII mRNA showed high therapeutic efficacy up to 15 days in vivo Ψ base modifications on mRNAs could improve therapeutic efficacy in liver- and endothelial-based therapeutics. Optimized mRNA synthesis for superior expression kinetics in hepatic cells and its delivery with liver-targeted nanoparticles may emerge as protein replacement therapies for monogenic liver disorders.1 Ψ base modifications on mRNAs could improve therapeutic efficacy in liver- and endothelial-based therapeutics. Optimized mRNA synthesis for superior expression kinetics in hepatic cells and its delivery with liver-targeted nanoparticles may emerge as protein replacement therapies for monogenic liver disorders.

Biosafety is a critical issue for the successful translocation of nanomaterial-based therapeutic/diagnostic agents from bench to bedside. For instance, after the withdrawal of clinically approved magnetic resonance (MR) imaging contrast agents (CAs) due to their biosafety issues, there is a massive demand for alternative, efficient, and biocompatible MR contrast agents for future MRI clinical applications. To this end, here we successfully demonstrate the in vivo MR contrast abilities and biocompatibilities of ligand-free FeSn 2 alloy NPs for tracking in vivo lung tumors. In vitro and in vivo results reveal the FeSn 2 alloy NPs acting as appreciable T 2 weighted MR contrast agents to locate tumors. The construction of iron (Fe) on biocompatible tin (Sn) greatly facilitates the reduction of the intrinsic toxicities of Fe in vivo resulting in no significant abnormalities in liver and kidney functions. Therefore, we envision that constructing ligand-free alloy NPs will be a promising candidate for tracking in vivo tumors in future clinical applications.

Uniform dispersion of Pd nanostructures supported on hydrothermally synthesized bimetal oxides on Ni foam substrate was successfully achieved by a simple electrochemical approach. The incorporated metal oxides provide excellent support and active surface area, which lead to superior electro-catalytic performance towards ethanol sensing applications. The synthesized nanocomposite materials were characterized by XRD, FE-SEM, HR-TEM, and EIS techniques, and their electrochemical behaviour was investigated using cyclic voltammetry and chronoamperometry techniques. The proposed sensor demonstrated excellent catalytic activity, high reproducibility, and long-term stability for ethanol electro-oxidation. In addition, the fabricated sensor displayed high sensitivity of 1277 μA mM−1 cm−2 in the concentration range from 0.1 to 2.1 mM with a limit of detection 0.7 μM. Enhancement in electro-catalytic activity is mainly due to the induced synergistic effect of metal oxide nanocomposite support that stabilizes the Pd NPs through the Pd–HO bond by the transfer of an electron to the PdNPs. This study paves the way for designing and constructing effective electro-catalysts that can be used in the real-time analysis of alcohol sensing. [ABSTRACT FROM AUTHOR]