# Selective mRNA Delivery to Activated Macrophages via Hyaluronic Acid-Functionalized Lipid Nanoparticles with Optimized PEGylation

## TL;DR

This study developed lipid nanoparticles coated with hyaluronic acid to selectively deliver mRNA to activated macrophages, improving targeting efficiency.

## Contribution

The study introduces optimized PEGylation and HA functionalization for selective mRNA delivery to activated macrophages.

## Key findings

- HA-LNP0.5%PEG showed better uptake in activated macrophages compared to HA-LNP1.5%PEG.
- Optimized PEGylation enhanced mRNA transfection efficiency and targeting selectivity.
- Excessive PEGylation hindered macrophage targeting, as shown by in vitro studies.

## Abstract

Activated proinflammatory macrophages are associated
with various
inflammatory diseases, and due to their overexpression of the CD44
receptor, they may be targeted for therapy by hyaluronic acid (HA),
its natural ligand. This study aimed to develop lipid nanoparticles
(LNPs) functionalized with HA and stabilized with an optimized amount
of poly­(ethylene glycol) (PEG) for targeted mRNA delivery to activated
macrophages. Using microfluidic mixing, LNPs were produced with either
1.5% PEG (LNP1.5%PEG) or 0.5% PEG (LNP0.5%PEG). HA-coated LNPs (HA-LNPs) were prepared by postinsertion of an
HA–DPPE conjugate, and changes in size and zeta potential demonstrated
a successful and efficient HA coating, which was quantified by spectrofluorimetry
and nanoscale flow cytometry. In vitro studies showed that HA-LNP0.5%PEG exhibited better uptake in activated macrophages while
maintaining mRNA transfection efficiency, whereas HA-LNP1.5%PEG did not improve its uptake, suggesting that excessive PEG can hinder
targeting. Overall, HA-LNP0.5%PEG effectively delivered
mRNA to activated macrophages with enhanced selectivity.