E20 is a charge-switching ionizable lipid developed for efficient nucleic acid delivery with reduced inflammatory toxicity. Its carboxylic acid–tertiary amine headgroup changes charge between acidic formulation conditions and physiological pH, while two hydroxylated spacers and branched 8×6 hydrophobic tails support nucleic acid encapsulation and cytosolic delivery. E20 nanoparticles generated approximately 600 mU/mL serum hEPO after intravenous mRNA administration in mice. Unlike multiple benchmark LNPs, E20 did not exacerbate cytokine production in LPS-pretreated mice or human PBMCs. E20 also enabled sustained pDNA expression without the acute lethality observed with MC3-LNPs and improved IL-22 mRNA treatment in a mouse model of acute lung injury. E20 remains a preclinical research lipid.

MIC2 is a set of multi-charged lipids with four tertiary amino nitrogen atoms (4N4T) which could be constructed and applied to form novel lipid nanoparticles developed by Westgen. 4N4T-LNPs based on MIC2 exhibit much higher mRNA translation efficiency than the approved SM-102-LNPs. 4N4T-LNPs are successfully applied to DS mRNA vaccine and the vaccines worked well against SARS-CoV-2 and its variants, including Delta and Omicron.

Imidazole cholesterol ester (ICE) is a sterol‑based ionizable cationic lipid invented by Translate‑Bio (WO2018/089790 A1) for mRNA‑loaded lipid‑nanoparticle (LNP) pulmonary delivery. It fuses an imidazole pH‑responsive headgroup with cholesterol via ester linkage. Typically formulated as a three‑component LNP (ICE : DOPE : DMG‑PEG2K = 60 : 35 : 5 mol ratio), ICE‑LNPs achieve high mRNA encapsulation (>80‑90 %), good nebulization stability and low toxicity. Upon cellular uptake, imidazole mediates endosomal escape; the ester bond degrades to yield cholesterol, conferring favorable biocompatibility. Animal studies demonstrate robust CFTR protein expression in bronchial and alveolar lung tissue after inhalation, making ICE promising for cystic‑fibrosis mRNA therapy.

TPN171 (TPN-171) is a highly potent, selective phosphodiesterase type 5 (PDE5) inhibitor with IC50 of 0.62 nM, 32-fold selectivity over PDE6.

MK-16(pKa 6.86) is a specialized lipid designed to traverse the blood-brain barrier (BBB) for effective mRNA delivery. Its formulation, MK 16 BLNP, leverages dual mechanisms involving caveolae and γ-secretase to facilitate BBB penetration, ensuring the targeted and efficient transport of functional mRNA to diverse brain cell types. Demonstrating excellent tolerability across a range of dosing regimens, MK16 BLNP represents a promising platform for brain-targeted therapeutic applications.

246C10 is a synthesized ionizable lipid. 246C10 can be formulated into lipid nanoparticles (LNPs) with dioleoylphosphatidylethanolamine (DOPE), cholesterol, and C16-PEG2000 ceramide (PEG-lipid) as well as mRNA. The lipid nanoparticle formulations can be used for mRNA delivery. To obtain iLNPs that could specifically target liver sinusoidal endothelial cells (LSECs), six different ionizable lipids (241C10 to 246C10) were synthesized by an epoxide ring-opening reaction with piperazine- or piperidine-containing amines. Biodistribution and gene regulation of various iLNPs were assessed in vivo, and the results showed that the 246C10 iLNPs (containing piperazine amine) had the highest luciferase expression in the liver. When further analyzing the 246C10 iLNPs transfection efficiency in different types of liver cells, it was found that tdTomato fluorescence was mainly concentrated in hepatocytes, not in LSECs. Figure 6f shows that 80% of hepatocytes are fluorescent, 40% of LSECs are fluorescent, and 20% of Kupffer cells are fluorescent. Due to the mannose receptor on LSECs, mannose-PEG lipid was introduced into 246C10 iLNPs to alter the distribution of iLNPs in different liver cells. As shown in Figure 6g, tdTomato fluorescence distribution was 15% of hepatocytes, 70% of LSECs, and 15% of Kupffer cells, significantly improved the ability of iLNPs to actively target LSECs. In contrast, this work indirectly shows that the iLNPs with piperazine head lipid are more able to deliver mRNA to the liver and translate the target protein than the iLNPs with piperidine head lipid. It is worth mentioning that the preparation buffer of 246C10 iLNPs could influence the encapsulation efficiency of mRNA. With the addition of sodium chloride in the citrate buffer, the encapsulation efficiency of CRISPR-Cas9 mRNA and sgRNA was increased. These iLNPs were able to treat hemophilia safely, without causing hepatotoxicity, the immune response induced by Cas9 and off-target editing.

11-10-8 is an ionizable cationic lipid (pKa = 6.22) that has been used in the generation of lipid nanoparticles (LNPs) for mRNA delivery in vivo.1 LNPs containing 11-10-8 and encapsulating mRNA encoding the Cas9 nuclease and small-guide RNA (sgRNA) targeting transthyretin (TTR), a thyroid hormone carrier protein, decrease serum levels of TTR in mice. LNPs containing 11-10-8 and encapsulating mRNA encoding human fibroblast growth factor 21 (hFGF21) increase serum levels of hFGF21, decrease body and liver weights, and reduce the liver steatosis score in a mouse model of obesity induced by a high-fat diet.

Icariside I is a metabolite of Icarlin, which could regulate bone remodeling and is recognized as an effective agent for the treatment of osteoporosis.

(20R)-Protopanaxdiol has protective effect on myocardial ischemia, which may be related to improving free radicals metabolism and myocardial metabolism, decreasing plasma TXA 2 levels.

SHR-1977 is a novel ROMK/hERG inhibitor, (ROMK IC50 = 44 nM, hERG IC50 = >100,000 nM)

XMD-18-42 is a NUAK1-sepcific inhibitor.

A novel VPS34 inhibitor.

CPI-455 analogue is a selective inhibitor of KDM5 demethylases.

HS-10 is a novel Hsp90 inhibitor increases the Tm of Hsp90 by 10.5°C.

Dac51 is a potent FTO inhibitor with IC50 of 0.4 μM, which blocks FTO-mediated immune evasion and synergize with checkpoint blockade for better tumor control.

NL1 is a select bacterial cystathionine γ-lyase (bCSE) inhibitor with IC50 of 5.8 μM (29.2 μM against hCSE). NL1 potentiates bactericidal antibiotics against pathogens.

Jun8-76-3A is a potent and selective noncovalent SARS-CoV-2 Mpro inhibitor with Ki of 0.07 μM. Jun8-76-3A only selectively inhibits SARS-CoV-2 and SARS-CoV Mpro, but not other viral proteases and host proteases including calpain 1, cathepsins L and K, and trypsin.

NL2 is a select bacterial cystathionine γ-lyase (bCSE) inhibitor with IC50 of 1.8 μM (25.3 μM against hCSE). NL2 potentiates bactericidal antibiotics against pathogens.

NL3 is a select bacterial cystathionine γ-lyase (bCSE) inhibitor with IC50 of 0.7 μM (3.4 μM against hCSE). NL3 potentiates bactericidal antibiotics against pathogens.

MCULE-3408819416|DC Chemicals

5,3-AB-CHMFUPPYCA is an analytical reference standard that is structurally classified as a synthetic cannabinoid.

Cortagine is a specific corticotropin-releasing factor receptor subtype 1 (CRF1) agonist with an IC50 of 2.6 nM for rCRF1. Cortagine is an anxiolytic and antidepressive drug in the mouse model.

Sortin3 is a sorting inhibitor, blocking Vps16 function, one protein in the class C tethering complex, and increasing aflatoxin synthesis and export.

N-0385 is a novel highly potent inhibitor of TMPRSS2-like proteases (IC50 = 1.9 nM) that blocks SARS-CoV-2 VOCs (B.1.1.7, P.1, B.1.351 and B.1.617.2) and is broadly protective against infection and mortality in mice. N-0385 demonstrates potent inhibition of SARS-CoV-2 infection in Calu-3 cells with EC50 of 2.8 nM and a SI of > 10E6.

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.

KC-34 (SPC-A9) is a novel stereopure, diketopiperazine-based ionizable cationic lipid engineered to overcome traditional liver-restricted delivery, achieving balanced multi-organ mRNA transfection. Upon systemic intravenous administration, its precisely optimized chiral configuration allows the lipid nanoparticles (LNPs) to efficiently cross endothelial barriers and target the bone marrow, offering immense therapeutic potential for in vivo hematopoietic stem cell gene editing. Concurrently, KC-34 mediates robust and long-lasting protein expression in the spleen and lungs with minimal hepatic off-target toxicity. Its stable structure provides excellent biocompatibility and high in vivo tolerance, making it ideal for systemic, multi-dose mRNA therapies.

BiP-20 is a branched ionizable phospholipid identified as a lead compound for efficient hepatic mRNA delivery.BiP-20 is a novel, efficient, and safe liver-targeted LNP delivery vehicle. With an ideal pKa of 6.56, it achieves highly efficient liver targeting and endosomal escape primarily through the ApoE/LDL-R pathway. It demonstrates exceptional performance in gene editing at very low doses: for CRISPR-Cas9-mediated editing of TTR, a 10 μg dose achieved ~64% efficiency, which is 8-fold higher than the clinical benchmark lipid LP-01. In Prime Editing targeting the PCSK9 gene, its efficiency (4.30%) also significantly surpassed that of MC3, SM102, and LPO1. Furthermore, it mediates a 5.9-fold increase in hepatic protein expression compared to MC3. Safety assessments indicate it does not induce liver function abnormalities, showing strong therapeutic potential.

L52715 is a novel ionizable lipid developed by Shanghai Vitalgen, used to deliver mRNA.