Ionizable liposomal siRNA therapeutics enables potent and persistent treatment of Hepatitis B

Abstract

Small interfering RNA (siRNA) constitutes a promising therapeutic modality supporting the potential functional cure of hepatitis B. A novel ionizable lipidoid nanoparticle (RBP131) and a state-of-the-art lyophilization technology were developed in this study, enabling to deliver siRNA targeting apolipoprotein B (APOB) into the hepatocytes with an ED50 of 0.05 mg/kg after intravenous injection. In addition, according to the requirements of Investigational New Drug (IND) application, a potent siRNA targeting hepatitis B virus (HBV) was selected and encapsulated with RBP131 to fabricate a therapeutic formulation termed RB-HBV008. Efficacy investigations in transient and transgenic mouse models revealed that the expressions of viral RNAs and antigens (HBsAg and HBeAg), as well as viral DNA, were repressed, dose-dependently and time-dependently at multilog decreasing amplitude, in both circulation and liver tissue. In contrast, entecavir (ETV), the first-line clinically-employed nucleoside analog drug, barely recused the antigen expression, although it triggered as high as 3.50 log reduction of viral DNA, in line with clinical observations. Moreover, the toxicity profiles suggested satisfactory safety outcomes with ten times the therapeutic window. Therefore, this study provides an effective nucleic acid delivery system and a promising RNAi agent for the treatment of hepatitis B.

Conscription of Immune Cells by Light‐Activatable Silencing NK‐Derived Exosome (LASNEO) for Synergetic Tumor Eradication

“…Rapid and efficient endosomal escape plays an essential role in siRNA delivery. [ 13 , 25 ] It was reported that ROS generated upon irradiation could interact with the lysosome/endosome membrane and facilitate siRNA escaping into the cytoplasm. It was assumed that ROS photogeneration in this study would disrupt both NEO and lysosome/endosome membrane, leading to effective siRNA escape and cytosolic release.…”

EVAnalyzer: High content imaging for rigorous characterisation of single extracellular vesicles using standard laboratory equipment and a new open‐source ImageJ/Fiji plugin

“…A prototypical application area is the LNP (lipid‐based nanoparticle) field, which has gained substantial momentum after the successful development and global application of LNP formulated mRNA vaccines for Covid19 (Baden et al., 2020 ). RNA encapsulation efficiencies by empty LNPs are typically determined indirectly such as by non‐membrane permeable RNA intercalating dyes (Huang et al., 2022 ; Michel et al., 2017 ; Wu et al., 2008 ), or fractions of RNA co‐isolating with liposomes, quantified by RT‐qPCR (Saha et al., 2018 ; Tsuji et al., 2016 ). We reasoned that quantitative single particle imaging enabled by EVAnalyzer might provide a straightforward and direct method to characterise RNA encapsulation at the single particle level.…”

mRNA-based modalities for infectious disease management

“…During lyophilization, the removal of water takes place via sublimation at low temperature under vacuum. Generally, lyophilization is comparatively a mild drying method and believed to enhance the stability issues mostly related to colloidal nanoparticles (NPs) and/or macro-biomolecules [145,146].…”