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Release of engineered extracellular vesicles for delivery of biotherapeutics

Objective

Nucleic acid-based medicines have opened a new avenue in drug discovery to target currently undruggable genes and to express therapeutic proteins, unlocking novel therapeutic options for a range of diseases, including neurodegeneration. However, they need to be encapsulated in nanocarriers to ensure their stability and efficient uptake into cells and tissues. Synthetic nanoparticles based on cell-penetrating peptides (CPPs) and, particularly, lipid nanoparticles (LNPs) have recently emerged as potent vectors for hepatic delivery. However, these systems fail to robustly target other organs in a safe manner.

Another promising nanocarrier for advanced drug delivery is extracellular vesicles (EVs) that have the ability to efficiently convey macromolecules into cells. As native nanoparticles, EVs benefit from immune tolerance as well as the ability to cross biological barriers to reach, for example, the brain. We have developed advanced strategies to bioengineer cells to generate EVs loaded with therapeutic RNAs and proteins. However, their production at scale is cumbersome and time consuming.

Here, I propose a platform development using synthetic nanocarriers to transiently engineer hepatic cells in vivo and harness EVs to functionally DELIVER biotherapeutics to currently unreachable, distant organs, focusing on brain. To achieve this, genetic constructs will be developed that allow for transient in situ engineering of cells in vivo and release of cargo (e.g. CRE)- laden EVs, displaying CNS-specific peptides, that can be functionally transported to distant organs, including brain. We will exploit the same strategy using CPP-based nanoformulations, recently developed in my lab, injected locally in brain to secrete EVs loaded with the disease-relevant protein GBA1 as a treatment strategy for Parkinson´s disease.

Long-term this novel project has enormous potential, as any engineered EV could be produced in situ and be used for delivery of virtually any biotherapeutics.

Field of science

  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins

Call for proposal

ERC-2020-COG
See other projects for this call

Funding Scheme

ERC-COG - Consolidator Grant

Host institution

KAROLINSKA INSTITUTET
Address
Nobels Vag 5
17177 Stockholm
Sweden
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 000 000

Beneficiaries (1)

KAROLINSKA INSTITUTET
Sweden
EU contribution
€ 2 000 000
Address
Nobels Vag 5
17177 Stockholm
Activity type
Higher or Secondary Education Establishments