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Generation of Cationic Nanoliposomes for the Efficient Delivery of In Vitro Transcribed Messenger RNA
Published on: February 1, 2019
Polylactide-Based Reactive Micelles as a Robust Platform for mRNA Delivery
Céline Lacroix1, Almudena Humanes1, Céline Coiffier1
1Biologie Tissulaire et Ingénierie Thérapeutique, IBCP, Université Lyon 1, CNRS, UMR 5305, 69367, Lyon, France.
Purpose:
mRNA has recently emerged as a potent therapeutics and requires safe and effective delivery carriers, particularly prone to address its issues of poor stability and escape from endosomes. In this context, we designed poly(D,L-lactide) (PLA)-based micelles with N-succinimidyl (NS) ester decorated hydrophilic hairy corona to trap/couple a cationic fusogenic peptide and further complex mRNA.
Methods:
Two strategies were investigated, namely (i) sequential immobilization of peptide and mRNA onto the micelles (layer-by-layer, LbL) or (ii) direct immobilization of peptide-mRNA pre-complex (PC) on the micelles. After characterization by means of size, surface charge, peptide/mRNA coupling/complexation and mRNA serum stability, carrier cytotoxicity and transfection capacity were evaluated with dendritic cells (DCs) using both GFP and luciferase mRNAs.
Results:
Whatever the approach used, the micellar assemblies afforded full protection of mRNA in serum while the peptide-mRNA complex yielded complete mRNA degradation. In addition, the micellar assemblies allowed to significantly reduce the toxicity observed with the peptide-mRNA complex. They successfully transfected hard-to transfect DCs, with a superior efficiency for the LbL made ones (whatever mRNAs studied) showing the impact of the elaboration process on the carrier properties.
Conclusions:
These results show the relevance and potential of this new PLA/peptide based micelle platform to improve mRNA stability and delivery, while offering the possibility of further multifunctionality through PLA core encapsulation.
Insights
This study developed poly(D,L-lactide) (PLA)-based micelles for messenger RNA (mRNA) delivery. The novel micellar carriers effectively protected mRNA from degradation and showed improved transfection in dendritic cells compared to peptide-mRNA complexes.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Drug Delivery Systems
Background:
- Messenger RNA (mRNA) therapeutics offer significant potential but face challenges in stability and endosomal escape.
- Effective delivery systems are crucial for mRNA's therapeutic applications.
Purpose of the Study:
- To design and evaluate poly(D,L-lactide) (PLA)-based micelles for enhanced mRNA delivery.
- To overcome mRNA instability and endosomal entrapment using a novel micelle platform.
Main Methods:
- Two strategies, layer-by-layer (LbL) and peptide-mRNA pre-complex (PC), were used to immobilize mRNA onto PLA micelles.
- Characterization included size, charge, mRNA protection, serum stability, cytotoxicity, and transfection efficiency in dendritic cells (DCs).
Main Results:
- Micellar assemblies provided complete mRNA protection in serum, unlike peptide-mRNA complexes which led to degradation.
- PLA micelles significantly reduced toxicity compared to peptide-mRNA complexes.
- The LbL approach demonstrated superior transfection efficiency in hard-to-transfect DCs.
Conclusions:
- The developed PLA/peptide micelle platform is a promising system for improving mRNA stability and delivery.
- This platform offers potential for further functionalization via PLA core encapsulation.
