Synthesis and Biological Evaluation of Ionizable Lipid Materials for the In Vivo Delivery of Messenger RNA to B Lymphocytes

TLDR

B lymphocytes play key roles in immunity, yet existing in vivo mRNA delivery systems predominantly target hepatocytes and dendritic cells, leaving B cells largely inaccessible. The study aims to develop a lipid nanoparticle capable of delivering mRNA to B lymphocytes in vivo. The authors synthesized a lipid nanoparticle that encapsulates mRNA, traffics to the spleen, and transfects B cells to produce over 60 pg of protein per million cells. The LNP achieved over 85 % of total protein production in the spleen and demonstrated that its composition alone can steer in vivo protein expression, underscoring the need for tailored nanomaterials.

Abstract

B lymphocytes regulate several aspects of immunity including antibody production, cytokine secretion, and T-cell activation; moreover, B cell misregulation is implicated in autoimmune disorders and cancers such as multiple sclerosis and non-Hodgkin's lymphomas. The delivery of messenger RNA (mRNA) into B cells can be used to modulate and study these biological functions by means of inducing functional protein expression in a dose-dependent and time-controlled manner. However, current in vivo mRNA delivery systems fail to transfect B lymphocytes and instead primarily target hepatocytes and dendritic cells. Here, the design, synthesis, and biological evaluation of a lipid nanoparticle (LNP) system that can encapsulate mRNA, navigate to the spleen, transfect B lymphocytes, and induce more than 60 pg of protein expression per million B cells within the spleen is described. Importantly, this LNP induces more than 85% of total protein production in the spleen, despite LNPs being observed transiently in the liver and other organs. These results demonstrate that LNP composition alone can be used to modulate the site of protein induction in vivo, highlighting the critical importance of designing and synthesizing new nanomaterials for nucleic acid delivery.