A Nanoprimer To Improve the Systemic Delivery of siRNA and mRNA

Abstract

Despite tremendous interest in gene therapies, the systemic delivery of nucleic acids still faces substantial challenges. To successfully administer nucleic acids, one approach is to encapsulate them in lipid nanoparticles (LNPs). However, LNPs administered intravenously substantially accumulate in the liver where they are taken up by the reticuloendothelial system (RES). Here, we administer prior to the LNPs a liposome designed to transiently occupy liver cells, the Nanoprimer. This study demonstrates that the pretreatment of mice with the Nanoprimer decreases the LNPs’ uptake by the RES. By accumulating rapidly in the liver cells, the Nanoprimer improves the bioavailability of the LNPs encapsulating human erythropoietin (hEPO) mRNA or factor VII (FVII) siRNA, leading respectively to more hEPO production (by 32%) or FVII silencing (by 49%). The use of the Nanoprimer offers a new strategy to improve the systemic delivery of RNA-based therapeutics.

Multicomponent Polymerization toward Cationic Polymers for Efficient Gene Delivery

“…Cationic polymers, also termed as polycations, are extensively recognized as ideal and promising nonviral gene delivery vectors toward clinical gene therapy. [ 1–6 ] With the ability to bind and neutralize the anionic charges of nuclear acids (such as DNA), polycations are capable of condensing and packing DNA into complexes (or polyplexes) and thus facilitating the efficient intracellular internalization. [ 7,8 ] Unfortunately, most of the polycations usually suffered from the cationic charges induced cytotoxicity, that is, polycations with high positive charges always exhibit superb transfection efficiency whereas associated with undesired cytotoxicity.…”

Nanoparticle‐mediated siRNA delivery systems for cancer therapy

“…44 The formulation of this P-MOF-siRNA nanoparticles incorporated 500 nm siRN siRNA loading. 45,46 As an integrated nanosystem, hybrid nanoparticles are holding promising potential for further translation and application into the clinic.…”

Therapeutic RNA Delivery for COVID and Other Diseases

“…Nanoprimer pretreatment increased mRNA delivery, quantified by the expression of human erythropoietin, as well as siRNA delivery, quantified by factor VII gene silencing. [ 17 ] One key question that will need to be addressed when saturating Kupffer cells, or other hepatic cell types that act as clearance cells when nonhepatic delivery is wanted (e.g., hepatocytes, endothelial cells, dendritic cells), is considered as a pretreatment is tolerability, especially given the potential role Kupffer cell activation may play in dose‐limiting and systemic nanoparticle‐mediated toxicity. [ 18 ] Specifically, authors found that platelet‐activating factor, likely released by Kupffer cells, was a key driver of the immune response from nanoparticles carrying siRNA.…”