Unravelling LNP endosomal escape

LNP are versatile drug and gene delivery particles. Examples of successful LNP formulation are the Comirnaty and mRNA-1273 Covid19 vaccines. Even though these are successful, cellular internalisation remains to be the man limiting factor on their therapeutic efficiency forcing high concentration doses with unwanted side effects. In-depth investigations using endosomal membrane mimics are limited due to the constrains of these systems. To meet this need, we developed an assay that monitors single LNP binding events to a supported lipid bilayer (SLB) designed to mimic the endosomal membrane. The SLB is formed on top of a nanoporous substrate that creates edges and compartments that facilitate molecular incorporation beneath the SLB. Neutron reflection will be used to demonstrate that the cationic lipid in LNP fuse with the membrane and that the cargo is delivered beneath the membrane.

脂质纳米粒（Lipid Nanoparticle，LNP）是一类多功能的药物与基因递送粒子。目前已实现成功应用的LNP制剂范例包括Comirnaty与mRNA-1273两款新冠疫苗。尽管此类制剂已取得良好效果，但细胞内吞作用仍是制约其治疗效能的主要瓶颈，该问题导致临床不得不采用高浓度给药方案，进而引发诸多不必要的不良反应。由于内体膜模拟系统存在诸多局限，针对该类体系的深入探究仍较为有限。为解决这一研究需求，本团队开发了一种检测方法，可监测单个LNP与模拟内体膜的支撑磷脂双层（supported lipid bilayer，SLB）的结合事件。该SLB构建于纳米多孔基底之上，该基底可形成边缘与腔室结构，助力分子嵌入SLB下方区域。本研究将借助中子反射（Neutron Reflection）技术，证实LNP中的阳离子脂质可与该模拟膜发生融合，并将递送载荷递送至膜下区域。