SS-cleavable and pH-responsive lipid-like material for gene, nucleic acids, and small molecule delivery system
SS-cleavable and pH-responsive Lipids COATSOME® SS Series
| Product Name | Structure | Mw |
|---|---|---|
| COATSOME SS-EC (ssPalm E-P4C2) |
|
1402.2 |
| COATSOME SS-OP (ssPalm O-Phe) |
|
1173.8 |
Patent No.: JP6093710, JP7298850, US9708628, US12064513
pH-Responsive Lipid Mechanism
This diagram illustrates the endosomal escape mechanism of pH-responsive ionizable lipids. Upon endocytosis, the tertiary amine groups become protonated in the acidic endosomal environment, promoting membrane fusion. After cytosolic entry, the disulfide bonds are reduced, enabling rapid cleavage and release of the encapsulated payload.
Proof of Concept
Particle Formation
Membrane Disruption in the Cells
The particle composed COATSOME® SS Series is stable inserum, hence enzymatic degradation of pDNA was prevented by encapsulation. Also the particle composed of COATSOME® SS Series was effectively destabilized in the cytoplasmic environment.
Degradation of COATSOME® SS-OP
High Degradable Type COATSOME® SS-OP
Accelerated degradability by phenyl ester contributes to improvement of delivery efficacy and low toxicity.
HPLC analysis
Lipid: COATSOME SS-OP (4mM total lipid)
Reagent: Glutathione (40mM) in PBS (pH7.4)
Reaction: 24 hour
Detection: Absorbance (PDA)
COATSOME SS-OP was completely degraded by addition of Glutathione.
In vivo toxicity in comparison to a competitor lipid
Hepatotoxicity
COATSOME® SS-OP is a highly degradable ionizable lipid engineered for efficient endosomal escape and rapid intracellular release. Its pH-responsive amine groups promote membrane fusion, while the disulfide linkage enables fast reductive cleavage inside cells, supporting effective delivery of nucleic-acid therapeutics.
Feature
- Encapsulation: siRNA, mRNA, pDNA
- Efficient drug delivery into the cytoplasm of cells
- Biodegradability and low toxicity
- Controlled targeting of organs: liver, spleen, or lymph nodes
- Long-term storage of lyophilized LNP at 25℃
- Application to freeze-thaw LNP
- Vaccine application (Humoral and Cellular immunity)
Formations
| Application | Nucleic acid | Recommended SS lipid |
|---|---|---|
| In vitro transfection | mRNA, pDNA | COATSOME® SS-OP |
| Liver targeting (I.V.) | siRNA | COATSOME® SS-OP |
| mRNA, pDNA | COATSOME® SS-OP | |
| Spleen targeting (I.V.) | mRNA, pDNA | COATSOME® SS-OP |
| Vaccine (cancer) (i.m., s.c.) | mRNA, pDNA | COATSOME® SS-OP+SS-EC |
| Vaccine (infection) (i.m., s.c.) | mRNA, pDNA | COATSOME® SS-OP |
| Topical administration | mRNA, pDNA | COATSOME® SS-OP |
Hepatic delivery of siRNA
Comparison of FVIl Knockdownefficacy in COATSOME® SS Series
LNP : SS-OP or SS-EC
Mouse: BALB/c, 6w, female
SiRNA: FVII 2'-F, 0.02mg/kg
Hepatic FVIl Knockdown Dose Dependency
Distribution of [3H] labeled LNPSS-EC
Hepatic Delivery of mRNA
Gene Editing (CRISPR/Cas9)
CTL Activity
Humoral Immunity
Therapeutic Anti-tumor Effect
Low-inflammatory LNP-based mRNA vaccine New
Antibody response against HA (Hemagglutinin) and NA (neuraminidase) of the influenza virus
Inflammatory Cytokine Production
Other cytokines (IFN-a, IF-B, IFN-y, CCL2, CXCL10) were produced at a similar tendency.
Adverse Reaction Following I.M Injection
"SS-OP" and "SM-102" notations in the figures on this page are modified from "LNP ssPalmO" and "LNP SM-102" in the reference; Kawai et al., Low-inflammatory lipid nanoparticle-based mRNA vaccine elicits protective immunity against H5N1 influenza virus with reduced adverse reactions, Molecular Therapy (2024), https://doi.org/10.1016/j.ymthe.2024.12.032). Molecular Therapy Vol. 33 No 2 February 2025 © 2024 The Authors).
Published by Elsevier Inc. on behalf of The American Society of Gene and Cell Therapy. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
in vitro transfection of mRNA
Splenic Delivery Formulation
Lyophilized LNP
Freeze-thaw LNP New
