Modular Design of Lipopeptide-Based Organ-Specific Targeting (POST) Lipid Nanoparticles for Highly Efficient RNA Delivery

Traditional lipid nanoparticles (LNPs) often suffer from non-specific hepatic accumulation, limiting their therapeutic potential for extrahepatic diseases. This study addresses this challenge by developing a modular screening strategy to create organ-specific targeting (POST) LNPs, aiming to improve the precision and efficiency of RNA delivery to specific tissues like the lung, liver, and spleen.

The researchers synthesized a library of 25 lysine-histidine-based lipopeptides (KH-LPs) using a one-pot ring-opening reaction. These lipopeptides were designed with varying peptide head lengths and aliphatic tails to balance charge and lipophilicity. By combining these KH-LPs with four different helper lipids (DOTAP, DOPE, DSPC, and 14PA), the team constructed a 100-member LNP library. They performed a multistage screening process, first in vitro using lung cancer cells (A549) to evaluate mRNA and siRNA transfection efficiency, followed by in vivo screening in mice to identify organ-specific delivery profiles.

The screening identified specific KH-LP/helper lipid combinations that achieved high organ-specificity. For instance, DOTAP-based POST LNPs demonstrated superior lung-targeting, while DOPE and DSPC-based formulations targeted the liver and spleen, respectively. These POST LNPs showed excellent stability, biocompatibility, and high silencing efficiency for target genes like PTEN, often outperforming established SORT (Selective Organ Targeting) LNP benchmarks. Structure-activity relationship (SAR) analysis revealed that different lipid systems have distinct preferences for lipopeptide structures, confirming that modular regulation is a viable strategy for optimizing RNA delivery vehicles.

This work provides a flexible, modular toolkit for designing next-generation gene delivery systems. By decoupling the targeting function (via helper lipids) from the transfection efficiency (via modular lipopeptides), researchers can more easily tune LNPs for specific therapeutic applications. This approach simplifies the development of targeted RNA therapies and offers a robust platform for treating diseases beyond the liver.