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Novel Discrete Immolative Guanidinium Transporters Deliver mRNA Selectively to the Spleen, Lungs, and Red Blood Cells, Reaching the Brain

Year: 2025
Type: article
Abstract: RNA-based therapeutics hold the potential to transform the prevention and treatment of disease with applications to therapeutic and prophylactic vaccinations, protein therapy, gene editing, cancer immunotherapy, and regenerative medicine. However, current systems used to deliver messenger RNA (mRNA), including those used in the COVID-19 vaccines, suffer from laborious syntheses, limited organ selectivity, formulation complexity, and undesired inflammatory responses mediated by the existence of persistently charged lipids in the body. This inspired the generation of a novel mRNA delivery system termed Discrete Immolative Guanidinium Transporters (DIGITs). Unlike most ionizable (ammonium) delivery systems, DIGITs are based on cationic guanidinium moieties, which complex mRNA at acidic pH and undergo irreversible charge neutralization at physiological pH to release their cargos in cells, enabling efficient RNA release and leaving behind neutral byproducts. Systematic evaluation of structural variations and formulations via in vivo bioluminescence assays, following delivery of fluorescent mRNA, led to the discovery of DIGIT/mRNA complexes that selectively target and deliver mRNA to the lungs, immune cells in the spleen, and even immature red blood cells in peripheral blood that can reach the brain. DIGIT/mRNA delivery systems, thus, provide a unique and innovative opportunity to develop cancer immunotherapies, personalized cancer vaccines, in vivo CAR T-cell therapies, and blood disorder and Alzheimer’s therapeutics, among other applications. This is supported by the finding that DIGIT/mRNA complexes are well-tolerated, following intravenous delivery, supporting their future utility in a variety of biomedical applications, affecting hundreds of millions of people worldwide.
DOI: 10.25740/jd931kj7152
Language: English
Open Access status: green
OpenAlex ID: W6908315226
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