Engineered internal architecture of core-shell lipid nanoparticles promotes efficient mRNA endosomal release

Area of Science:

• Biotechnology
• Nanomedicine
• Drug Delivery

Background:

• Messenger RNA (mRNA) therapeutics require efficient delivery vehicles like lipid nanoparticles (LNPs).
• Inefficient endosomal escape limits mRNA's access to the cytoplasm, hindering therapeutic potential.
• Current LNPs with amorphous cores struggle with protonation-driven membrane disruption.

Purpose of the Study:

• To engineer novel LNPs with improved internal structure for enhanced mRNA delivery.
• To investigate the role of ionizable lipid-coated gold nanoparticles (IC-AuNPs) as rigid, pH-responsive cores in LNPs.
• To overcome the bottleneck of endosomal escape in mRNA therapeutics.

Main Methods:

• Development of core-shell LNPs utilizing IC-AuNPs as internal cores.
• Characterization of LNP architecture and pH-responsive properties.
• In vitro and in vivo assessment of endosomal escape, mRNA diffusion, and therapeutic outcomes.

Main Results:

• Engineered Au-core LNPs demonstrated a twofold increase in endosomal escape compared to conventional LNPs.
• Achieved approximately 100-fold greater cytoplasmic mRNA diffusion with Au-LNPs.
• Enhanced in vitro mRNA expression, up to sevenfold increase in in vivo protein production.
• Improved antibody responses to SARS-CoV-2 vaccines and therapeutic efficacy in a triple-negative breast cancer model.

Conclusions:

• The novel Au-LNP architecture significantly enhances mRNA endosomal escape and cytoplasmic delivery.
• This strategy offers a promising approach for improving mRNA therapeutics, including vaccines and cancer treatments.
• The pH-responsive, rigid gold nanoparticle core is key to amplifying LNP performance under endosomal conditions.