Lipids for Bone-Marrow RNA Delivery

CICL 207 is structurally optimized based on Lipid CICL-1. CICL207​​ is a constrained ionizable cationic lipid designed for lipid nanoparticle (LNP) delivery systems developed by Capstan. Its structure features a ​​rigid cyclic backbone​​ (e.g., pyrrolidine-derived core) paired with a ​​tertiary amine group​​ that ionizes at acidic pH (pKa ~6.5–7.0), enhancing endosomal escape. The lipid includes ​​asymmetric hydrophobic tails​​ (likely C14–C18 alkyl/ester chains) to stabilize LNP membranes and improve nucleic acid encapsulation. Integrated into LNPs (e.g., 58% CICL-207, 10% DSPC, 30.5% cholesterol, PEG-lipids), it enables targeted delivery to T cells (anti-CD5/CD8 tLNPs) with ​​high transfection efficiency​​ (spleen T cells >70% mCherry+), ​​reduced liver uptake​​, and ​​low toxicity​​ (no significant ALT/AST elevation in rats). Its constrained design balances stability, tissue specificity, and biocompatibility for gene therapy applications.CICL 207 (F50) significantly outperforms CICL-1 by delivering dramatically enhanced target cell transfection with reduced off-target effects. It achieves >50% transfection efficiency in splenic T-cells—nearly double that of CICL-1—while slashing off-target expression in liver cells to <5% (versus >15% for CICL-1. This precision translates to superior therapeutic outcomes: CICL-207 enables ~95% B-cell depletion in CAR-T applications, far exceeding CICL-1 ’s ~60% efficacy. Critically, it maintains an exceptional safety profile, showing no significant liver toxicity or inflammatory cytokine elevation even at high doses. Furthermore, CICL-207 demonstrates 2-fold higher transfection efficiency in hematopoietic stem cells, enabling robust gene editing. Its optimized pKa (~6.5) and constrained amine structure enhance endosomal escape while minimizing Kupffer cell uptake, making it ideal for targeted therapeutics requiring both potency and safety.​

Lipid 87 is a proprietary ionizable lipid developed by Generation Bio. Used as a key ingredient in stealth LNPs, it greatly prolongs blood circulation time, maintains high nucleic acid encapsulation efficiency and low cytotoxicity, and enables effective liver targeting. Its relevant applications are documented in PCT patent WO2026/080826A1. As a core component (47.5–57.5 mol%) of stealth lipid nanoparticles (LNPs), it works synergistically with steric-stabilizing polymers like DSG-PEG₂₀₀₀-OMe to extend the in vivo blood half-life of LNPs to over 24 hours (compared to merely 30 minutes of conventional LNPs). It achieves an encapsulation efficiency above 95% for mRNA and closed-ended DNA (ceDNA), exhibits low cytotoxicity with an IC₅ value greater than 100 μM, and delivers robust liver-targeting performance, obtaining over 80% hepatocyte transfection at a dosage of 0.5 mpk. In preclinical models of hemophilia B, LNPs formulated with Lipid 87 can restore around 40% of clotting factor IX (FIX) activity for more than seven days.

CICL1 (L829)​​ is a ​​novel ionizable cationic lipid​​ specifically engineered for ​​targeted lipid nanoparticles (tLNPs)​​ that enables efficient in vivo delivery of mRNA payloads to ​​CD8+ T cells​​. Designed to overcome limitations of conventional LNPs, CICL-1 (L-829)​​significantly ​​reduces off-target delivery to the liver​​ and exhibits ​​rapid clearance​​ compared to benchmark lipids like ALC-0315, while demonstrating ​​enhanced biodegradability and tolerability​​ in rodent and primate models. When incorporated into CD8-targeted tLNPs, CICL 1 (L829 enables ​​preferential transfection of CD8+ T cells​​ over other immune subsets, facilitating the generation of functional ​​anti-CD19 or anti-CD20 CAR T cells directly *in vivo​​*. These tLNP-engineered CAR T cells mediate ​​rapid, deep B-cell depletion​​ in humanized mice and cynomolgus monkeys, with repopulating B cells exhibiting a naïve phenotype suggestive of immune reset. By eliminating the need for ex vivo manufacturing or lymphodepleting chemotherapy, the L829-tLNP platform represents a ​​safer, scalable approach​​ for accessible CAR T therapy in oncology and autoimmune diseases.

ALC-0315 is an ionisable aminolipid that used for mRNA compaction and aids mRNA cellular delivery. ALC-0315 can be used to form lipid nanoparticle (LNP) delivery vehicles.

5A2-SC8 is a dendrimer for miRNA delivery to late-stage liver tumors with low hepatotoxicity. 5A2-SC8 shows potent EC50 < 0.02 mg/kg (siRNA against FVII (siFVII)) in dose-response experiments, and well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven tumors. 5A2-SC8 is a degradable lipid-like compound (ester-based dendrimer) for small RNAs delivery.5A2-SC8, was obtained by screening a large library of more than 1500 ester-based dendrimers containing ionizable amino groups, which have three tertiary amine heads and five lipid tails. Based on this library, the in vitro transfection efficiency of different formulations of 5A2-SC8 iLNPs was evaluated, discovering the optimal formulation (5A2-SC8, DOPE, cholesterol, PEG at a molar ratio of 15:15:30:3) of 5A2-SC8 iLNPs for delivering fumarylacetoacetate hydrolase (FAH) mRNA to liver.After the intravenous injection via tail, the model mice of hepatorenal tyrosinemia type I had strong FAH protein expression, which prevented body weight loss and increased the survival rate of hepatorenal tyrosinemia mice . In addition to introducing utility of 5A2-SC8 iLNPs for the therapeutic intervention, the 5A2-SC8 iLNPs containing DOTAP have been used to establish complex mouse models via intravenous injection, including in situ liverspecific cancer model and in situ lung-specific cancer model. Based on this iLNPs delivery system, 5A2-SC8 induced model construction method overcomes the time-consuming and costly disadvantages of traditional animal models establishing methods, including transgenesis and gene engineering in embryonic stem cells.

SM-102 is an ionizable amino lipid that has been used in combination with other lipids in the formation of lipid nanoparticles.Administration of luciferase mRNA in SM-102-containing lipid nanoparticles induces hepatic luciferase expression in mice. Formulations containing SM-102 have been used in the development of lipid nanoparticles for delivery of mRNA-based vaccines.

LIPID168(pKa ~6.5) ​​ is an optimized ionizable lipid engineered for in vivo mRNA delivery to hematopoietic stem cells (HSCs) in bone marrow. Developed by ​​Yoltech Therapeutics​​ through high-throughput screening of lipid libraries, it features a ​​diethylamino head group​​ and a tailored hydrophobic tail structure that enables antibody-free targeting. When Lipid 168 was formulated into lipid nanoparticles (LNPs), it achieved ​​48.5% base editing efficiency​​ in bone marrow cells —surpassing benchmarks like LIPID-028 (19.7%)—and reduced off-target liver editing from 71% to 19% by incorporating ​​miR-122 target sequences​​. In humanized β-thalassemia models, LNP 168 delivered ABE8e mRNA/sgRNA to patient-derived HSCs, yielding ​​42.6% editing at the HBG promoter​​, reactivating fetal hemoglobin (γ-globin) and rescuing erythroid defects . Its bone marrow specificity is driven by a unique ​​protein corona​​ enriched in albumin, fibronectin, and fibrinogen . Safety studies confirmed transient immune responses and no cumulative toxicity . LIPID-168 represents a promising non-viral platform for curative gene therapies in blood disorders.

H5T5 is a leading ionizable lipid nanoparticle (LNP) formulation optimized for in vivomRNA delivery, featuring a pKa of 6.51, a size of ~154 nm, and a narrow polydispersity index (PDI) of 0.05. It demonstrated superior in vitromRNA transfection efficiency in primary immune cells, such as bone marrow-derived macrophages. Following intravenous administration, H5T5 exhibits precise organotropism, predominantly targeting the spleen and bone marrow, where it effectively delivers mRNA to a broad spectrum of immune cells, including macrophages, dendritic cells, T cells, B cells, and NK cells. This capability enables its core application: the in vivogeneration of "pan-CAR" immune cells. When loaded with anti-HER2 CAR mRNA, the H5T5-based therapy achieved potent tumor regression and prolonged survival in multiple solid tumor models. Preliminary safety assessments indicated a manageable cytokine profile and no significant organ toxicity, positioning it as a promising platform for in vivocell engineering.

Lipid A10 (CSS-A10) is a diketopiperazine-core ionizable lipid used in the LNP67 formulation for mRNA delivery to hematopoietic stem and progenitor cells. In the cited study, ligand-free LNP67 delivered reporter mRNA to mouse bone-marrow HSC/HSPC populations and to CD34+ cells in young rhesus monkeys after intravenous administration.

Lipid 10 is a novel ionizable cationic lipid be used for delivery of therapeutic RNA to the Bone Marrow in Multiple Myeloma Using CD38-Targeted with Lipid 10-LNP.

a12Dab4 is a novel, high-performance peptide-based ionizable lipid designed specifically as the core functional building block for lipid nanoparticles (LNPs) targeting challenging or quiescent cell types, such as human hematopoietic stem and progenitor cells (HSPCs). Chemically engineered to possess a unique peptide-mimetic backbone, it provides superior membrane fusion and exceptional endosomal escape capabilities compared to older-generation, industry-standard lipids like Dlin-MC3-DMA and ALC-0315. Functionally, its primary role within the LNP formulation is to complex and efficiently encapsulate sensitive nucleic acid payloads, such as mRNA or CRISPR/Cas9 editing machinery, at an optimal nitrogen-to-phosphate (N/P) ratio. When formulated, a12Dab4 enables maximum cellular transfection and robust genome editing while exhibiting minimal cytotoxicity and preserving the long-term proliferative, self-renewing functionality of primitive stem cell compartments. Although it delivers commendable baseline transfection independently, it functions as an exceptional molecular chassis that synergies seamlessly with surface antibody conjugation (such as anti-CD34) to unlock precise, therapeutic-grade in vivo gene engineering.

C14-490 is an ionizable cationic lipid (pKa = 5.94).1 It has been used in the generation of lipid nanoparticles (LNPs) for the delivery of mRNA in vivo.C14-490-containing LNPs accumulate primarily in the fetal mouse liver and, to a lesser extent, in the lungs, intestine, and brain after vitelline vein injection on gestational day 16 (E16).1 CD45-functionalized LNPs containing C14-490 and encapsulating mRNA encoding GFP transfect Jurkat cells, which constitutively express the CD45 receptor (CD45R).C14-490-containing CD45-functionalized LNPs encapsulating Cre mRNA mediate genome modulation in bone marrow hematopoietic stem cells (HSCs) for at least four months after in utero injection in R26mT/mG mice at E13.5.