Beyond the Liver to the Whole Body: Designing Novel Lipid Structures for Precise mRNA Delivery
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Current limitation: mRNA carriers that preferentially accumulate in the liver As demonstrated by COVID-19 vaccines, mRNA technology is revolutionary, yet a major challenge remains. Conventional lipid nanoparticles (LNPs) tend to accumulate in the liver after intravenous administration, limiting the development of therapeutics that target other organs such as the lung, muscle, or tumor.
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Innovative approach: analysis of structure-function relationships The research team systematically designed new constructs beyond simple lipid structures, including lipid analogs and lipid-like polymers.
Structure-function relationship: The team deeply analyzed the ‘design principles’ governing how the physicochemical properties of an mRNA-bearing carrier dictate its organ tropism.
Identification of common elements: A shared genomic design basis that enables efficient delivery performance and specific organ or cell targeting was uncovered.
- Major outcomes: organ-specific customizable targeting Applying the established design principles allows precise delivery of mRNA to sites beyond the previous limitations, including:
- Lungs and respiratory tract: prevention of infectious diseases and treatment of lung cancer
- Muscle tissue: therapy for genetic disorders such as muscular dystrophy
- Tumor tissue: next-generation anticancer vaccines that selectively strike cancer cells
- Outlook: a new horizon for personalized gene therapy This work provides a critical platform for evolving mRNA therapeutics from liver-focused treatments to a universal platform capable of addressing diverse diseases throughout the body. The development of these new materials is expected to accelerate the era of personalized mRNA vaccines and therapeutics tailored to each patient’s disease location.
The application of mRNA therapies has witnessed significant advancement since the outbreak of COVID-19. However, the widespread use of mRNA therapies has been restricted by the liver accumulation of traditional lipid structures used as delivery vectors. The efficacy of mRNA expression has been demonstrated to be highly related to vector structures and properties. To expand non-liver organs or cells as therapeutic targets for mRNA, lipid and other lipid-like molecules such as lipid analogs and lipid-like polymers with more favorable mRNA delivery efficiencies have been developed based on a deeper understanding of their structure-function correlations. This review primarily summarizes the structure commonalities leading to an excellent delivery performance and specific organ or cell targeting and illustrates the potential and future prospects of related materials in different biomedical applications of mRNA therapies.
If delivery systems move beyond liver-focused targeting, mRNA therapeutics can be applied to a broader range of diseases, substantially expanding healthcare accessibility. Moreover, non-liver targeting offers societal benefits by reducing side effects and improving therapeutic efficacy.