Title: Mechanisms and optimization of endosomal escape for cell delivery applications Controlled manipulation of cells through the precise intracellular delivery of biologically active materials has been a long-term goal for probing of cellular mechanisms and therapeutic interventions. Cellular delivery is however a problem that has not yet been solved. Most techniques remain inefficient, are disruptive to cells and can be toxic. Furthermore, no single approach works for all macromolecular cargo, across cell types, or in every context (e.g. cell cultures vs in vivo). This problem is exacerbated by emerging biological applications continually pushing the boundaries of required delivery efficiencies and versatility (e.g. CRISPR-Cas9 technologies). This project aims to reveal fundamental mechanisms of how to permeate cellular membranes, enabling precise control of the molecules that achieve this cell permeation, and to develop new platforms for cellular delivery. Thus, the proposed studies will significantly advance both understanding and solutions to the cell delivery problem.

Public Health Relevance

Title: Mechanisms and optimization of endosomal escape for cell delivery applications Reagents that can deliver proteins or nucleic acids inside live cells have the potential of revolutionizing the development of therapeutics for the treatment of human diseases. Currently, a major bottleneck in the field is that protein or nucleic acid therapeutics cannot penetrate cells efficiently. This project aims to solve this problem by developing reagents that make macromolecules cross membranes..

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM110137-05
Application #
9740687
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Garcia, Martha
Project Start
2015-06-01
Project End
2023-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Texas A&M Agrilife Research
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
847205713
City
College Station
State
TX
Country
United States
Zip Code
77843
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Lian, Xizhen; Huang, Yanyan; Zhu, Yuanyuan et al. (2018) Enzyme-MOF Nanoreactor Activates Nontoxic Paracetamol for Cancer Therapy. Angew Chem Int Ed Engl 57:5725-5730
Lian, Xizhen; Erazo-Oliveras, Alfredo; Pellois, Jean-Philippe et al. (2017) High efficiency and long-term intracellular activity of an enzymatic nanofactory based on metal-organic frameworks. Nat Commun 8:2075
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Najjar, Kristina; Erazo-Oliveras, Alfredo; Brock, Dakota J et al. (2017) An l- to d-Amino Acid Conversion in an Endosomolytic Analog of the Cell-penetrating Peptide TAT Influences Proteolytic Stability, Endocytic Uptake, and Endosomal Escape. J Biol Chem 292:847-861
Wang, Ting-Yi; Pellois, Jean-Philippe (2016) Peptide translocation through the plasma membrane of human cells: Can oxidative stress be exploited to gain better intracellular access? Commun Integr Biol 9:e1205771
Robison, Aaron D; Sun, Simou; Poyton, Matthew F et al. (2016) Polyarginine Interacts More Strongly and Cooperatively than Polylysine with Phospholipid Bilayers. J Phys Chem B 120:9287-96
Wang, Ting-Yi; Sun, Yusha; Muthukrishnan, Nandhini et al. (2016) Membrane Oxidation Enables the Cytosolic Entry of Polyarginine Cell-penetrating Peptides. J Biol Chem 291:7902-14

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