Brain-targeted delivery

MK16 is an MK-0752-derived ionizable lipid developed for blood-brain-barrier-crossing mRNA delivery in preclinical mouse models. In the cited MK16 BLNP formulation, the authors reported an apparent LNP pKa of 6.86, a particle diameter of 137.0 ± 4.1 nm, 84.8 ± 1.5% mRNA encapsulation, and brain FLuc expression 8.3-fold above an MC3 LNP comparator after intravenous administration. The study also reported mRNA expression in neurons, astrocytes, brain capillary endothelial cells and microglia, as well as proof-of-concept results in cocaine-conditioned-place-preference and orthotopic glioblastoma models. All formulation and performance information shown below is literature-derived study evidence, not a product specification or a guarantee of reproducible LNP performance.

Lipid S4 is an advanced ionizable lipid engineered for systemic mRNA delivery to the brain, leveraging SR-57227—a high-affinity 5-HT3 receptor ligand—as its core head group to enable targeted blood-brain barrier (BBB) penetration via receptor-mediated transcytosis, while incorporating amino linkers for pH-responsive ionization and biodegradable branched ester tails to facilitate efficient endosomal escape and intracellular mRNA release; optimized through orthogonal screening into OS4 LNP (formulated at S4/DOPE/Chol/DMG-PEG2k = 40:40:60:0.75 molar ratio), it demonstrated a 13.3-fold increase in brain mRNA expression compared to FDA-approved MC3 LNPs, and further conjugation with the Tat cell-penetrating peptide yielded OS4T LNP, boosting delivery efficiency by 12.7-fold over OS4 alone and enabling broad mRNA expression across neurons, astrocytes, microglia, and endothelial cells; validated in orthotopic glioblastoma models, OS4T delivered engineered IL-12 mRNA, suppressing tumor growth and extending median survival to 37 days (vs. 17 days for controls) with minimal systemic toxicity, positioning S4-based LNPs as a robust, translatable platform for CNS-targeted therapeutics.

C12-4 (Lipid A-4,Lipid F3) is a branched-chain ionizable cationic lipidoid that has been used in the formation of lipid nanoparticles (LNPs) for the delivery of mRNA. LNPs containing lipid A4 and encapsulating an mRNA reporter accumulate in the uterus, placenta, and ovaries, as well as to the spleen and liver, in pregnant mouse dams unlike LNPs containing the branched-chain ionizable cationic lipidoid C12-200, which primarily accumulate in the liver. Intravenous administration of LNPs containing lipid A4 and encapsulating mRNA encoding VEGF increase placental VEGFR1 levels and mean fetal blood vessel area without inducing liver damage in pregnant mouse dams.

NT1-O12B, an endogenous chemical and a neurotransmitter-derived lipidoid (NT-lipidoid), is an effective carrier for enhanced brain delivery of several blood-brain barrier (BBB)-impermeable cargos. Doping NT1-O12B into BBB-impermeable lipid nanoparticles (LNPs) gives the LNPs the ability to cross the BBB. NT-lipidoids formulation not only facilitate cargo crossing of the BBB, but also delivery of the cargo into neuronal cells for functional gene silencing or gene recombination.

NT1-O14B is a tryptamine-containing cationic lipidoid.1 It has been used in combination with other lipids in the formation of lipid nanoparticles (LNPs). Intravenous administration of LNPs containing NT1-O14B and encapsulating antisense nucleotides against tau decreases tau brain levels in mice.

F10T5 is a furan-derived ionizable lipid developed for mRNA delivery to the central nervous system through the meningeal lymphatic pathway. Its architecture incorporates an ionizable polyamine region and four hydrophobic tails containing acid-sensitive acetal linkages. Following subcutaneous administration near the deep cervical lymph nodes, F10T5 LNPs enabled functional mRNA expression in neurons, microglia, and astrocytes while producing relatively low signals in peripheral organs. Cre mRNA delivery resulted in tdTomato expression in approximately 8.93% of neurons, 7.0% of microglia, and 9.9% of astrocytes in mice. Compared with the co-lead lipid F11T6, F10T5 showed comparable total brain luciferase expression, stronger astrocyte transfection, and lower peripheral-organ distribution. Its activity was associated primarily with improved endosomal escape rather than increased cellular uptake. F10T5 remains a preclinical research lipid, and its repeat-dose safety, pharmacokinetics, and performance in larger animals require further evaluation.

C14-306 is a rationally designed ionizable lipid for brain targeting delivery, characterized by a linear 3,3'-diamino-N-methyldipropylamine (306) core conjugated with tetradecyl (C14) tails. This specific architectural configuration, synthesized via epoxide ring-opening amination, yields a molecular structure that optimally balances hydrophobic character and protonation capacity. The C14 alkyl chains enhance membrane integration and LNP stability, while the multiamine core facilitates efficient mRNA complexation and pH-dependent endosomal disruption. When formulated into LNPs with standard helper lipids (DOPE, cholesterol, DMG-PEG2000), C14-306-based nanoparticles exhibit favorable physicochemical properties, including a monodisperse size distribution near 110 nm and high mRNA encapsulation efficiency (>84%). High-throughput in vivo barcoding screening identified C14-306 LNPs as lead candidates for brain delivery, demonstrating a significant tropism for neuronal cells over liver tissue. In validation studies, LNPs incorporating C14-306 achieved a 6.9-fold increase in luciferase mRNA transfection in the mouse brain compared to the SM-102 benchmark, coupled with a substantial reduction in hepatic off-target expression. Flow cytometry confirmed preferential transfection of NeuN+ neurons, and safety assessments indicated no significant blood-brain barrier compromise or induction of systemic inflammation. The efficacy of C14-306 is attributed to its tailored pKa, promoting extended circulation and enhanced endosomal escape within brain cells. C14-306 represents a promising platform for systemic mRNA therapeutics targeting neurological disorders.

P3B is a biodegradable ionizable lipid engineered to function as a highly efficient delivery vehicle for genome-editing machinery (e.g., CRISPR-Cas9 and adenine base editors) specifically to the central nervous system (CNS). Its primary function is to encapsulate and transport large mRNA payloads across the brain-CSF interface following intrathecal administration, enabling robust and widespread gene editing in neurons and astrocytes across multiple brain regions, including the hippocampus, cortex, and thalamus. Notably, it facilitates precise single-nucleotide correction via base editing. Its targeting is intrinsically achieved by the intrathecal injection route, which localizes the nanoparticles within the cerebrospinal fluid, coupled with an optimized formulation that promotes efficient uptake and activity within CNS parenchyma while minimizing off-target exposure in peripheral organs.

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.

CA2d is an ionizable lipid developed for systemic mRNA delivery to the central nervous system. Its architecture combines an MK-0752-derived CNS-accessing moiety, a short three-carbon diamine spacer, a tertiary ionizable amine, and two acetal-containing hydrophobic tails. When formulated with DOPE, cholesterol and DMG-PEG2000, CA2d LNPs crossed the blood-brain barrier through caveolae- and γ-secretase-associated transcytosis and delivered mRNA to neurons, astrocytes, microglia and brain endothelial cells. Following intravenous administration of FLuc mRNA at 0.5 mg/kg in mice, CA2d produced 16.6-fold higher brain expression than MC3 and 8.6-fold higher expression than SM-102 at 6 hours. CA2d was further evaluated in repeated brain-cell transfection studies, a pilot rhesus macaque experiment and a tPA-modified TGF-β1 mRNA formulation for ischemic stroke. These results support CA2d as a promising preclinical research lipid for investigating non-viral CNS mRNA delivery; it has not been clinically validated.

306-O12B-3 is an ionizable lipidoid with cationic properties, commonly used in lipid nanoparticle (LNP) formulations for antisense oligonucleotide (ASO) delivery. When administered intravenously in mice, LNPs incorporating 306-O12B-3 exhibit liver-specific accumulation. Studies show that ASO-loaded LNPs containing 306-O12B-3 effectively silence hepatic PCSK9 expression by targeting the proprotein convertase subtilisin/kexin type 9 gene. Additionally, when combined with the cationic lipidoid NT1-O14B (Item No. 37095), these LNPs can deliver tau-targeting ASOs to the brain, reducing tau protein levels in mice.

Lipid 8 iLNPs were used to deliver CRISPR-Cas9 mRNA and sgRNA which targeted to the PLK1 gene. The safety and excellent intracerebral diffusion performance of lipid 8 iLNPs ensured that the survival of murine glioblastoma multiforme (GBM) mice was extended. The median survival was extended by approximately 50% and the overall survival was increased by 30%. The treatment of metastatic adenocarcinoma was executed by the EGFRtargeted lipid 8 iLNPs. These iLNPs possessed the ability of tumor targeting, which could increase the accumulation of CRISPR-Cas9 mRNA and sgRNA within the tumor cells. After a single intraperitoneal administration,
80% PLK1 gene was edited and the overall survival of mice with high-grade ovarian cancer malignant ascites was enhanced by
80% . These results demonstrate the clinical potential of CRISPR-Cas9 gene editing system can be delivered by iLNPs for treating tumors, and provide new ideas for tumor gene therapy.

Lipid 51 is a top-performing thioglycerol-based biodegradable ionizable lipid disclosed in PCT patent WO2026/147683 (Eli Lilly, filed Dec 16, 2025). Built with cleavable thioester linkages, it balances neutral surface charge at physiological pH and protonatable amines in acidic endosomes for efficient mRNA encapsulation and endosomal escape. Formulated into LNPs with DSPC, cholesterol and DMG-PEG2K, it exhibits favorable particle size, low PDI and high RNA loading efficiency. In intracerebroventricular (ICV) mouse tests targeting central nervous system (CNS), it delivers Cre mRNA to brain neurons far more potently than Lipid 1/2/3, with the highest tissue fluorescent signal among all tested candidates. It shows low cellular toxicity in vitro and robust CNS tropism, making it an optimal carrier for brain-targeted mRNA and CRISPR gene editing therapeutics.

DEA‑14‑DAP is a novel ionizable cationic SORT lipid. As a key component for central nervous system targeting, it enables lipid nanoparticles (LNPs) to specifically target microglia, significantly improving the delivery efficiency and cellular selectivity of nucleic acid drugs in the brain.

C6O2B2 is a cholesterol-conjugated cationic/ionizable lipid developed for ligand-free mRNA delivery to brain endothelial cells following intravenous administration. Its architecture combines a piperazine-containing polyamine core, four degradable ester-linked hydrophobic tails, and a covalently attached cholesterol moiety through a flexible five-carbon spacer. Among 51 newly synthesized cholesterol-based lipids, C6O2B2 produced the strongest brain luciferase expression. An optimized LNP formulation containing C6O2B2, DODAP, DSPC, and DMG-PEG enabled efficient functional mRNA expression throughout the cerebral vascular network, with preferential transfection of CD31-positive brain endothelial cells and minimal detectable neuronal or glial expression. The formulation preserved BBB integrity in Evans blue and contrast-enhanced MRI assessments. Mechanistic studies associated its activity with improved membrane fusion, enhanced endosomal escape, and ApoA-I enrichment in the protein corona. Delivery of IL-10 mRNA also reduced vascular leakage and inflammatory cytokines in a mouse model of acute neuroinflammation. C6O2B2 remains a preclinical research lipid requiring further pharmacokinetic and repeat-dose evaluation.

F11T6 is a next-generation lipid nanoparticle (LNP) optimized for ultra-efficient neuron-targeted mRNA delivery, featuring a dual-tetrahydrofuran (THF) core and four pH-responsive acetal tails. Its unique bis-THF architecture enhances lipid bilayer stability and promotes brain-specific biodistribution, achieving ​​16.4% GFP+ neurons​​ in vivo—the highest reported among CNS-targeting LNPs. Cryo-EM reveals a compact spherical structure (Ø~150 nm) with 93.2% mRNA encapsulation efficiency, while THF-acetal synergy enables rapid endosomal escape (Pearson coefficient: 0.16 vs. 0.27 for F10T5). Preclinical studies show F11T6 leverages meningeal lymphatic transport for brain accumulation, yielding ​​13.0% neuron-specific tdTomato expression​​ in Ai14 mice, surpassing F10T5 (8.93%) and SM102 (0.1%). Mechanistically, the dual-THF core strengthens interactions with lipoprotein receptors on brain endothelial cells, whereas acetal tails undergo acid-triggered hydrolysis in endosomes, releasing mRNA into the cytoplasm. Despite slightly higher liver/spleen accumulation than F10T5, toxicology assessments confirm no hepatorenal toxicity (BUN/ALT/AST within normal ranges) or histopathological changes. Co-localization analyses demonstrate superior penetration into deep brain regions like the hippocampus, critical for treating neurodegenerative disorders. With a LogD of 12.3, F11T6 balances lipid solubility and biodegradability, outperforming clinical benchmarks in both efficiency (40× SM102) and neuron specificity. This platform holds transformative potential for delivering CRISPR-Cas9, siRNA, or neurotrophic factors, particularly in diseases demanding high-dose CNS transfection with minimal off-target effects.