Restoring hematopoietic stem and progenitor cell function in mice by delivery of RNA lipid nanoparticles.

Fanconi anemia (FA) is a congenital multisystem disorder characterized by early-onset bone marrow failure (BMF) and cancer susceptibility. While gene addition and repair therapies are being considered as treatment options, depleted hematopoietic stem cell (HSC) pools, poor HSC mobilization, compromised survival during transduction, and increased sensitivity to conventional conditioning strategies limit eligibility for FA patients to receive gene therapies. As an alternative approach, we explored protein replacement by mRNA delivery via lipid nanoparticles (LNPs).

Multiarm-Assisted Design of Dendron-like Degradable Ionizable Lipids Facilitates Systemic mRNA Delivery to the Spleen.

Lipid nanoparticles (LNPs) have emerged as pivotal vehicles for messenger RNA (mRNA) delivery to hepatocytes upon systemic administration and to antigen-presenting cells following intramuscular injection. However, achieving systemic mRNA delivery to non-hepatocytes remains challenging without the incorporation of targeting ligands such as antibodies, peptides, or small molecules. Inspired by comb-like polymeric architecture, here we utilized a multiarm-assisted design to construct a library of 270 dendron-like degradable ionizable lipids by altering the structures of amine heads and multiarmed tails for optimal mRNA delivery.

Toward a Complete Elucidation of the Primary Structure-Activity in Pentaerythritol-Based One-Component Ionizable Amphiphilic Janus Dendrimers for In Vivo Delivery of Luc-mRNA.

Four-component lipid nanoparticles (LNPs) and viral vectors are key for mRNA vaccine and therapeutics delivery. LNPs contain ionizable lipids, phospholipids, cholesterol, and polyethylene glycol (PEG)-conjugated lipids and deliver mRNA for COVID-19 vaccines to liver when injected intravenously or intramuscularly. In 2021, we elaborated one-component ionizable amphiphilic Janus dendrimers (IAJDs) accessing targeted delivery of mRNA.

Placenta-tropic VEGF mRNA lipid nanoparticles ameliorate murine pre-eclampsia.

Pre-eclampsia is a placental disorder that affects 3-5% of all pregnancies and is a leading cause of maternal and fetal morbidity worldwide. With no drug available to slow disease progression, engineering ionizable lipid nanoparticles (LNPs) for extrahepatic messenger RNA (mRNA) delivery to the placenta is an attractive therapeutic option for pre-eclampsia. Here we use high-throughput screening to evaluate a library of 98 LNP formulations in vivo and identify a placenta-tropic LNP (LNP 55) that mediates more than 100-fold greater mRNA delivery to the placenta in pregnant mice than a formulation based on the Food and Drug Administration-approved Onpattro LNP (DLin-MC3-DMA).