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A multiobjective AI model for LNP engineering enhances tissue-selective mRNA delivery.

Muye Zhou1, Yue Xu1, Gen Li1

  • 1Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.

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|April 28, 2026
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Summary

Researchers developed an AI system (MOLEA) to engineer lipid nanoparticles (LNPs) for precise RNA delivery. This approach enhances therapeutic targeting, significantly improving tissue selectivity and reducing off-target toxicity, as demonstrated in cartilage applications.

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Area of Science:

  • Biotechnology
  • Artificial Intelligence
  • Drug Delivery

Background:

  • Lipid nanoparticle (LNP) delivery of RNA therapeutics faces challenges with poor tissue selectivity and off-target toxicity.
  • Current high-throughput screening methods often prioritize single-target efficacy over off-target uptake.
  • Developing LNPs with both high potency and biological selectivity is crucial for effective RNA therapeutics.

Purpose of the Study:

  • To engineer ionizable lipids for RNA therapeutics with improved tissue selectivity and reduced off-target toxicity.
  • To develop a multiobjective LNP engineering system using artificial intelligence (AI).
  • To identify LNPs that preferentially deliver mRNA to target tissues while minimizing off-target transfection, such as in hepatocytes.

Main Methods:

  • Integration of high-dimensional lipid representations with cell-type-resolved transfection data.
  • Application of multitask optimization within an AI framework (MOLEA).
  • Learning structure-function relationships across diverse cellular contexts to guide lipid design.

Main Results:

  • Development of K9 LNPs for cartilage targeting, achieving >90% transfection efficiency in mouse joint chondrocytes.
  • Demonstrated a 13.5-fold increase in knee-to-liver selectivity compared to the clinical benchmark SM-102.
  • Showcased chondrocyte-specific Mmp13 editing in osteoarthritis mouse models, leading to sustained cartilage protection and disease suppression.

Conclusions:

  • AI-guided multiobjective optimization enables precision RNA delivery.
  • The MOLEA system can design potent and selective ionizable lipids for targeted RNA therapeutics.
  • This approach holds potential for advancing RNA delivery applications in various tissues beyond cartilage.