Our Science
A solution to endosomal entrapment
The Problem: Endosomal Entrapment
RNA therapeutics possess high target selectivity, efficacy and produce a broad range of cellular effects. However, their size and physical/chemical properties prevent them from passing directly through cell membranes. Instead, RNA drugs enter through receptor-mediated endocytosis or bulk-phase pinocytosis. Once endocytosed, they accumulate in small compartments called endosomes and lysosomes. Without an efficient mechanism to pass through the endosomal membrane, they largely remain trapped and are eventually degraded or exported from the cell. Failure to reach the cell cytosol precludes these novel drugs from reaching their intracellular targets and providing a therapeutic benefit.
Without endosomal release, drugs that bind cell surface receptors and are shuttled into the endosomal pathway eventually enter lysosomes where they are degraded by lysosomal enzymes. In the absence of a cytosolic delivery system, less than 2% of an RNA drug[1] will reach the cytosol and exert a therapeutic effect.
1. Dowdy SF, Setten RL, Cui XS, Jadhav SG. Delivery of RNA Therapeutics: The Great Endosomal Escape! Nucleic Acid Ther. 2022 Oct;32(5):361-368.
A Solution for Intracellular Drug Delivery
Our endosomal release (ER) peptide effectively releases co-localized or attached RNA therapeutics and other biomacromolecules from the late endosome or lysosome into the cytosol.
The ER peptide, endocytosed along with the drug, traffics through the endo-lysosomal pathway. As the pH drops, the peptide undergoes changes that allow it to enter the lysosomal membrane and facilitate drug release.
ER Peptide
The ER peptide has a modular design with distinct functionalities that address challenges in intracellular drug delivery.
Select a feature in the graphic to read more
The Active Segment
The Active Segment releases biomacromolecules from the late endosome/lysosome for effective intracellular delivery.
Cleavable Segment
Cleaved in the late endosome/lysosome, the Cleavable segement frees the Active segment from the Mask.
Preventing non-specific entry
Charge-charge repulsion between the acidic ER peptide and anionic groups on the cell surface prevent non-specific cell entry.
Mask Segment
The Mask segment reduces binding of the peptide to serum albumin in the blood to improve bioavailability.
Targeting Group
A targeting group mediates cell entry. Targeting groups can be antibodies, nanobodies, aptamers, sugars, small molecules, etc.
Advantages
Efficacy
With effective release of your drug from the lysosome into the cytosol, you’ll be able to lower doses while achieving greater therapeutic efficacy.
Targeting
Charge-charge repulsion between our anionic peptide and cell surfaces prevents unintended cell entry, ensuring cell targeting is governed by the targeting group.
Circulation
Improved circulation for drugs and cell targeting groups where rapid clearance by the liver and kidneys is a problem. The ER peptide provides a moderate amount of serum albumin binding improving circulation without compromising drug bioavailability.
Current Initiatives
Our goal is the integration of our endosomal release peptide with Antibody-Oligo Conjugates for improved delivery and more effective treatments for patients.
Seeking Collaborations
Are you in academia, biotech or pharma? Are you working on an RNA therapeutic or other drug with an intracellular target? Do you have a cell targeting group? We are looking for collaborations. Please contact us to discuss possibilities.