Lipids for Circular RNA Delivery

iL-19 is an aminoethoxy-functionalized ionizable lipid with a triamine scaffold, two ester linkages and four doubly branched hydrophobic tails. It was identified as the overall lead for circular RNA delivery in a 2026 JACS study. With circRNA encoding firefly luciferase, iL-19 LNPs produced approximately 28-fold higher expression than the SM-102 benchmark in C2C12 cells and approximately 2.5-fold higher expression after intramuscular administration in BALB/c mice under the reported conditions. The reported circRNA formulation uses iL-19, DSPC, cholesterol and DMG-PEG2000 at 50:10:38.5:1.5 mol%. It supports preclinical investigation of circular RNA delivery to muscle; comprehensive safety and immunogenicity evaluation remains outstanding.

PL-40​​ is a ​​cardiolipin-mimetic ionizable lipid​​ engineered for high-efficiency, antibody-free mRNA delivery to T cells. PL 40 LNPs exhibit a mean particle size of ​​120 nm​​, zeta potential of ​​-5.19 mV​​, and >80% mRNA encapsulation efficiency, with excellent plasma stability (≤5% size change after 6h in serum). Cryo-TEM reveals ​​polyhedral nanoparticles​​ with phase-separated domains, while SAXS confirms tight mRNA packing (d-spacing: ​​~3 nm​​ vs. 6.64 nm in conventional LNPs). AFM demonstrates exceptional rigidity (high bending modulus), enabling T cell-selective uptake via actin-mediated endocytosis (>2× higher than ALC0315 LNPs).In primary human T cells, PL40 LNPs achieve ​​>90% transfection​​ at 0.5 μg mRNA dose and sustain >100× higher luciferase expression than benchmark lipids. When delivering circular RNA, they extend protein expression ​​>5 days​​ with superior spleen tropism (spleen:liver ratio = ​​2.63​​). Crucially, they reprogram T cells into functional CAR-Ts in vivo without antibody conjugation, evading exhaustion markers (no Tim-3/PD-1 upregulation). Therapeutically, PL40-based uPAR-targeted CAR mRNA reduces liver fibrosis (​​collagen↓50%​​, ALT↓50%) and rheumatoid arthritis severity (​​clinical scores↓60%​​) by clearing senescent cells. Humanized anti-uPAR CARs delivered via PL40 show near-complete cytotoxicity (>95%) against uPAR+ cells, underscoring clinical translatability.

D-Lin-MC3-DMA(MC3) is the most potent cationic lipid that has been synthesized for Lipid nanoparticles (LNPs) to deliver the siRNA.

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.

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.

Lipid 10a-26​​ is an ionizable lipid developed by Orna Therapeutics for lipid nanoparticle (LNP) formulations. Lipid 10a-26 is a key ionizable lipid in the LNP-6 formulation. Through structural modification, it exhibits reduced binding to ApoE proteins and lowered liver affinity compared to traditional ionizable lipids. Instead, Lipid 10a-26 demonstrates strong splenic tropism—in non-human primate studies, it effectively delivers payloads to the spleen and immune cells in peripheral blood, such as T cells, NK cells, and macrophages, enabling the possibility of "in vivo CAR-T" therapy. Its pKa is tuned to approximately 6.0–6.5, allowing rapid protonation in the acidic endosomal environment, which promotes endosomal membrane disruption and efficient cytosolic release of circular RNA.

AP60 is a novel, biomimetic ionizable lipid, identified as the lead compound from a library of 67 aminophosphonate-derived lipids. Inspired by the structure of natural phospholipids, it forms the core component of lipid nanoparticles within the CROSS delivery platform. AP60-based LNPs demonstrate superior efficiency in delivering mRNA and circular RNA to neuronal cells and astrocytes compared to the clinically used MC3 LNP. In a mouse model of spinal cord injury, AP60 LNPs achieved significantly higher protein expression at the lesion site (13.7-fold locally, 4.6-fold intravenously) while concurrently reducing off-target accumulation in the liver by nearly 5-fold. This indicates improved targeting to the central nervous system injury site and a potentially better safety profile. Its cellular uptake is primarily mediated by clathrin-mediated endocytosis and macropinocytosis, followed by efficient endosomal escape. By encapsulating therapeutic circular RNAs encoding Sox2, Ascl1, and GDNF, AP60 LNPs enable effective in vivo reprogramming and neuroprotection, leading to significant functional recovery of bladder and locomotor functions after spinal cord injury.

FL0445 is a biodegradable, multi-branched ionizable lipid featuring an ionizable amine-containing headgroup together with ester and carbonate linkages. When formulated with DOPE, cholesterol, and a PEG lipid, FL0445-LNP enabled efficient delivery of both linear mRNA and structurally constrained capped circular RNA (Cap-cirRNA). In the reported study, the optimized formulation produced substantially higher in vitro protein expression than benchmark LNPs based on MC3, SM-102, or ALC-0315 and demonstrated functional nucleic-acid delivery following intravenous, intramuscular, and subcutaneous administration in mice. The platform was also evaluated for mRNA vaccination, ASO-mediated gene silencing, pDNA delivery, and GLP-1-encoding Cap-cirRNA. FL0445-LNP induced comparatively low inflammatory cytokine responses and showed favorable single-dose tolerability in the tested mouse models, supporting its further evaluation as a versatile preclinical delivery lipid for mRNA, circular RNA, and other nucleic-acid modalities.

H1L1A1B3 is an ionizable lipid which demonstrates a fourfold increase in circRNA transfection efficiency in lung cancer cells over ALC-0315. H1L1A1B31 is capable of proactively stimulating innate immune activation upon injection.

Lipid CP-LC-0729, an ionizable cationic amino lipid synthesized from homocysteine—a naturally occurring amino acid—has been shown to exhibit superior efficacy in the delivery and subsequent protein expression of various RNA modalities, including messenger RNA (mRNA), circular RNA (cRNA), and self-amplifying RNA (saRNA) in vivo. Importantly, CP-LC-0729 demonstrates an exemplary safety profile, with no observable toxicological effects in preclinical studies. Comparative analyses reveal that CP-LC-0729 significantly surpasses MC3, a widely utilized benchmark lipid nanoparticle formulation, in terms of protein expression efficiency. Specifically, CP-LC-0729 achieves a striking 32-fold enhancement in protein expression within lung tissue relative to MC3, underscoring its pronounced tissue selectivity and targeting efficacy for pulmonary applications. These findings suggest that CP-LC-0729 represents a highly promising candidate for the development of RNA-based therapeutics, particularly in the context of lung-targeted delivery systems, where its combination of high efficiency and low toxicity offers significant translational potential.

CP-LC-0867 is listed as a ionizable lipid for laboratory research use.

Lipid U 105 is an ionizable cationic lipid (pKa 6.65) specifically designed for circular RNA delivery via LNPs. These formulations effectively enhance VEGF-A expression in HUVECs, promoting endothelial cell proliferation and migration. When applied topically in diabetic mouse models, the VEGF-A-encoding circular RNA LNPs significantly accelerate wound healing, demonstrating therapeutic potential for impaired tissue repair.