[DALL-E]

Hitched to Lipid Rafts: Targeting Cells with Surgical Precision

A groundbreaking study from Northwestern University reveals a new technique to deliver engineered proteins to specific cells, revolutionizing targeted biological drug delivery
Engineered Human Therapies
by
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July 18, 2024

Scientists at Northwestern University have developed a groundbreaking method to hijack cellular delivery systems, using tiny virus-sized containers to deliver engineered proteins to specific cells. This breakthrough could revolutionize the field of targeted biological drug delivery, paving the way for more effective treatments for various diseases. The key to this success lies in encouraging engineered proteins to move toward specific cell membrane structures, which increases the likelihood of the protein latching onto the container.

Published recently in Nature Communications, the paper argues that this novel technique could be generalizable, paving the way for the ultimate goal of targeted biological drug delivery.

This study represents a significant step forward in addressing a major bottleneck in biological medicine development: determining how to protect fragile molecules in the body and ensure they reach the correct diseased cells without affecting healthy ones. The research brings together the work of two labs at Northwestern’s Center for Synthetic Biology: the lab of biomedical engineer Neha Kamat focused on designing synthetic containers and using biophysical principles to control molecule targeting, and the lab of chemical and biological engineer Josh Leonard, which develops tools to build natural delivery containers known as extracellular vesicles (EVs).

“We were interested in applying some of the biophysical insights that have emerged about how to localize proteins to specific membrane structures so that we could hijack this natural system,” said Kamat, co-corresponding author and associate professor at the McCormick School of Engineering. “In this study, we discover general ways to load drug cargo into these vesicles very efficiently while preserving their function. This might enable more effective and affordable extracellular vesicle-based biological medicines.”

The key to this “cargo loading” approach lies in sites on cell membranes called lipid rafts. These regions are more structured than the rest of the membrane and reliably contain specific proteins and lipids.

“Lipid rafts are thought by some to play a role in the genesis of EVs, as EV membranes contain the same lipids found in lipid rafts,” said Justin Peruzzi, who co-led the study with Taylor Gunnels as doctoral students in Kamat’s lab. Gunnels continues his work in the lab, while Peruzzi, having completed his Ph.D., now works as a scientist at a protein-based medicine company. “We hypothesized that if we engineered proteins to associate with lipid rafts, they may be loaded into the vesicles, allowing them to be delivered to other cells.”

The team used protein databases and lab experiments to determine that lipid raft association is an efficient method for loading protein cargo into EVs, enabling up to 240 times more protein to be loaded into vesicles.

After uncovering this biophysical principle, the researchers demonstrated a practical application of the method. They engineered cells to produce a transcription factor protein, loaded it into EVs, and delivered it to a cell, altering the recipient cell’s gene expression without compromising the protein’s function.

Kamat and Leonard highlighted the main challenge in loading therapeutic cargo into EVs: the producer cell and the recipient cell often have conflicting requirements. In the producer cell, therapeutic cargo might need to tightly associate with a membrane to increase its chances of moving into a soon-to-be-released EV. However, this behavior can be undesirable in the recipient cell, where the cargo might need to release from the EV membrane and move to the nucleus to function. The solution lies in creating cargo with reversible functions.

“Tools that enable reversible membrane association could be really powerful when building EV-based medicines,” said Gunnels. “Although we’re not yet sure of the precise mechanism, we see evidence of this reversibility with our approach. We were able to show that by modulating lipid-protein interactions, we could load and functionally deliver our model therapeutic cargo. Looking forward, we’re eager to use this approach to load therapeutically relevant molecules, like CRISPR gene-editing systems.”

The researchers are eager to test the approach with medicinal cargo for applications in immunotherapy and regenerative medicine.

“If we can load functional biomedicines into EVs that are engineered to only deliver those biomolecules to diseased cells, we can open the door to treating all sorts of diseases,” said Leonard, co-corresponding author and McCormick professor. “Because of the generalizability we observed in our system, we think this study’s findings could be applied to deliver a wide array of therapeutic cargos for various disease states.”

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Hitched to Lipid Rafts: Targeting Cells with Surgical Precision

by
July 18, 2024
[DALL-E]

Hitched to Lipid Rafts: Targeting Cells with Surgical Precision

A groundbreaking study from Northwestern University reveals a new technique to deliver engineered proteins to specific cells, revolutionizing targeted biological drug delivery
by
July 18, 2024
[DALL-E]

Scientists at Northwestern University have developed a groundbreaking method to hijack cellular delivery systems, using tiny virus-sized containers to deliver engineered proteins to specific cells. This breakthrough could revolutionize the field of targeted biological drug delivery, paving the way for more effective treatments for various diseases. The key to this success lies in encouraging engineered proteins to move toward specific cell membrane structures, which increases the likelihood of the protein latching onto the container.

Published recently in Nature Communications, the paper argues that this novel technique could be generalizable, paving the way for the ultimate goal of targeted biological drug delivery.

This study represents a significant step forward in addressing a major bottleneck in biological medicine development: determining how to protect fragile molecules in the body and ensure they reach the correct diseased cells without affecting healthy ones. The research brings together the work of two labs at Northwestern’s Center for Synthetic Biology: the lab of biomedical engineer Neha Kamat focused on designing synthetic containers and using biophysical principles to control molecule targeting, and the lab of chemical and biological engineer Josh Leonard, which develops tools to build natural delivery containers known as extracellular vesicles (EVs).

“We were interested in applying some of the biophysical insights that have emerged about how to localize proteins to specific membrane structures so that we could hijack this natural system,” said Kamat, co-corresponding author and associate professor at the McCormick School of Engineering. “In this study, we discover general ways to load drug cargo into these vesicles very efficiently while preserving their function. This might enable more effective and affordable extracellular vesicle-based biological medicines.”

The key to this “cargo loading” approach lies in sites on cell membranes called lipid rafts. These regions are more structured than the rest of the membrane and reliably contain specific proteins and lipids.

“Lipid rafts are thought by some to play a role in the genesis of EVs, as EV membranes contain the same lipids found in lipid rafts,” said Justin Peruzzi, who co-led the study with Taylor Gunnels as doctoral students in Kamat’s lab. Gunnels continues his work in the lab, while Peruzzi, having completed his Ph.D., now works as a scientist at a protein-based medicine company. “We hypothesized that if we engineered proteins to associate with lipid rafts, they may be loaded into the vesicles, allowing them to be delivered to other cells.”

The team used protein databases and lab experiments to determine that lipid raft association is an efficient method for loading protein cargo into EVs, enabling up to 240 times more protein to be loaded into vesicles.

After uncovering this biophysical principle, the researchers demonstrated a practical application of the method. They engineered cells to produce a transcription factor protein, loaded it into EVs, and delivered it to a cell, altering the recipient cell’s gene expression without compromising the protein’s function.

Kamat and Leonard highlighted the main challenge in loading therapeutic cargo into EVs: the producer cell and the recipient cell often have conflicting requirements. In the producer cell, therapeutic cargo might need to tightly associate with a membrane to increase its chances of moving into a soon-to-be-released EV. However, this behavior can be undesirable in the recipient cell, where the cargo might need to release from the EV membrane and move to the nucleus to function. The solution lies in creating cargo with reversible functions.

“Tools that enable reversible membrane association could be really powerful when building EV-based medicines,” said Gunnels. “Although we’re not yet sure of the precise mechanism, we see evidence of this reversibility with our approach. We were able to show that by modulating lipid-protein interactions, we could load and functionally deliver our model therapeutic cargo. Looking forward, we’re eager to use this approach to load therapeutically relevant molecules, like CRISPR gene-editing systems.”

The researchers are eager to test the approach with medicinal cargo for applications in immunotherapy and regenerative medicine.

“If we can load functional biomedicines into EVs that are engineered to only deliver those biomolecules to diseased cells, we can open the door to treating all sorts of diseases,” said Leonard, co-corresponding author and McCormick professor. “Because of the generalizability we observed in our system, we think this study’s findings could be applied to deliver a wide array of therapeutic cargos for various disease states.”

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