TD5 is a brain-targeting lipid nanoparticle (BLNP) engineered for efficient mRNA delivery to the central nervous system (CNS) via intrathecal injection. It incorporates a tryptamine-derived ionizable lipid headgroup, myristic acid hydrocarbon tails, and a biodegradable carbonate ester linker, enabling pH-dependent mRNA encapsulation (81.7% efficiency) and brain cell-specific targeting. With a hydrodynamic diameter of 107.5 nm, near-neutral pKa (7.30), and mild positive charge, TD 5 demonstrates superior CNS tropism through serotonin receptor (5-HT1A)-mediated endocytosis. In vitro, TD-5 achieved 80.8% GFP expression in SH-SY5Y neuronal cells, outperforming MC3 LNPs by 50-fold. Following intrathecal administration in mice, TD-5 mediated GFP expression in 29.6% of neurons and 38.1% of astrocytes brain-wide, with 10-fold higher CNS specificity than peripheral organs. Genome editing studies showed TD5-delivered Cas9/sgRNA induced tdTomato activation in ≈30% of neurons and 40% of astrocytes across key brain regions. Safety profiling revealed minimal systemic immune responses (lower IL-6, IL-12p40 vs MC3 LNPs), normal hepatic/renal biomarkers, and no histopathological toxicity. The optimized structure balances myristic chain hydrophobicity for membrane interaction, ionizable amines for mRNA complexation, and tryptamine-mediated targeting for enhanced CNS uptake, establishing TD5 as a promising platform for CNS gene therapies.
Cat.No
DC67521
Name
Lipid TD5
Chemical Properties
CAS
2855180-86-6
Formula
C45H81N3O
MW
679.64
Storage
2 years -20°C Powder, 2 weeks 4°C in DMSO, 6 months -80°C in DMSO
References
Dong, Y. et.al Lipid Nanoparticles Enhance mRNA Delivery to the Central Nervous System Upon Intrathecal Injection. Adv. Mater. 2025, e2417097.
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