Technology

Entrada Therapeutics’ intracellular biologics platform allows molecules like proteins, peptides and nucleic acids to be efficiently delivered into the cell

Entrada’s delivery vehicles boast improved bioavailability, biodistribution, metabolic stability and enhanced efficiency compared to previous gold standards. Our technology increases the therapeutic window and enables repeat dosing in a safe, predictable and controlled manner.

Entrada is advancing intracellular enzyme replacement therapy (IC-ERT) programs for the treatment of rare, monogenic diseases where patients are deficient in a key intracellular enzyme. Additionally, Entrada is advancing intracellular protein-protein interaction (PPI) inhibitor programs and the delivery of nucleic acids. We are creating the next-generation of therapeutics against previously undruggable intracellular targets.

Biologics generally cannot enter the cell

Many molecules, such as proteins, peptides and nucleic acids, have highly potent and specific biological activities in vitro.

These molecules are usually hydrophilic and large in size, are unable to penetrate the cell membrane and therefore are not effective therapeutic agents against intracellular targets.

Entrada’s technology leverages endocytic uptake

Through biocompatible conjugation, Entrada’s technology enables the intracellular delivery of cargo that are not cell-permeable.

An Entrada biologic consists of a proprietary peptide conjugated to its cargo. The proprietary peptide induces rapid endocytic uptake of the Entrada biologic into the cell.

Entrada’s technology facilitates endosomal escape

After entering the cell, Entrada biologics are initially localized in endosomes and subsequently efficiently escape from the endosomes into the cytosol.

In addition to general cytosolic delivery (as illustrated), Entrada biologics can also be engineered to target specific organelles inside the cell.

Functional intracellular delivery

After being released into the cytosol, the conjugated cargo (e.g. a protein, peptide or nucleic acid) is able to function normally and address the underlying cause of a disease.

For Entrada’s IC-ERT programs, the conjugated cargo addresses a genetic intracellular enzyme deficiency.

For Entrada’s PPI inhibitor programs, the conjugated cargo blocks a disease-causing protein-protein interaction.

Publications

Non-peptidic cell-penetrating motifs for mitochondrion-specific cargo delivery

  • In: Angew. Chem. Int. Ed. 57
  • By: Appiah Kubi, G, Qian, Z, Amiar, S, Sahni, A, Stahelin, RV, and Pei, D
View online
2018

Discovery and mechanism of highly efficient cyclic cell-penetrating peptides

  • In: Biochemistry 55, 2601-2612
  • By: Qian, Z, Martyna, A, Hard, RL, Wang, J, Appiah-Kubi, G, Coss, C, Phelps, MA, Rossman, JS, and Pei, D
View online
2016

Early endosomal escape of a cyclic cell-penetrating peptide allows effective cytosolic cargo delivery

  • In: Biochemistry 53, 4034-4046
  • By: Qian, Z, LaRochelle, JR, Jiang, B, Lian, W, Hard, RL, Selner N, Luechapanickhul, R, Barrios, AM, and Pei, D
View online
2014

Efficient delivery of cyclic peptides into mammalian cells with short sequence motifs

  • In: ACS Chem. Biol. 15, 423-431
  • By: Qian, Z, Liu, T, Liu, Y, Briesewitz, R, Barrios, AM, Jhiang, SM, Pei, D
View online
2013