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Testing the In Vitro and In Vivo Efficiency of mRNA-Lipid Nanoparticles Formulated by Microfluidic Mixing
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High-Throughput In Vivo Screening Identifies Structural Factors Driving mRNA Lipid Nanoparticle Delivery to the

Emily L Han1, Dongyoon Kim1, Amanda M Murray1

  • 1Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.

ACS Nano
|January 20, 2026
PubMed
Summary

Researchers developed novel ionizable lipid nanoparticles (LNPs) for messenger RNA (mRNA) brain delivery. A specific LNP formulation, C14-306, successfully delivered mRNA to the brain with reduced liver transfection and no observed toxicity.

Keywords:
braindrug deliverylipid nanoparticlesmRNAnanomedicine

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Area of Science:

  • Nanomedicine
  • Neuroscience
  • Biotechnology

Background:

  • Systemic nonviral delivery of large nucleic acids like messenger RNA (mRNA) to the brain faces significant challenges, including the blood-brain barrier (BBB) and off-target delivery.
  • Ionizable lipid nanoparticles (LNPs) offer a modular platform for fine-tuning nucleic acid delivery, showing promise for targeted applications.

Purpose of the Study:

  • To investigate how ionizable lipid chemical structure and lipid molar ratios in LNPs influence mRNA delivery and transfection within the brain.
  • To identify specific LNP formulations that enhance brain delivery while minimizing off-target effects.

Main Methods:

  • Employed a high-throughput in vivo screening approach utilizing mRNA barcoding to evaluate a large library of LNPs.
  • Systematically varied ionizable lipid structures, ionizable lipid amounts, and lipid-polyethylene glycol (PEG) amounts within the LNP formulations.
  • Conducted safety analyses to assess BBB integrity, inflammatory cytokine levels, and liver enzyme levels.

Main Results:

  • Identified that ionizable lipids with longer tail structures and linear amine cores facilitate mRNA delivery to the mouse brain.
  • Discovered a specific ionizable lipid, C14-306, that enhances brain transfection and reduces liver transfection compared to an FDA-approved benchmark.
  • Demonstrated that the lead LNP formulation with C14-306 increases neuronal transfection and facilitates Cre-mediated recombination in the brain without inducing BBB leakage or significant systemic toxicity.

Conclusions:

  • Molecular barcoding is a valuable tool for high-throughput screening of LNPs for brain delivery.
  • Specific ionizable lipid structures and formulations can be engineered to achieve targeted mRNA delivery to the brain.
  • The identified C14-306 LNP formulation represents a promising advancement for brain-tropic nucleic acid delivery with a favorable safety profile.