Biomimetic liposomes enable PROTAC delivery across endothelial barriers
- 6 hours ago
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Scientists from the research group of PROXIDRUGS PI Prof. Maike Windbergs at Goethe University Frankfurt have developed a biomimetic nanocarrier strategy that enables PROTAC delivery across an endothelial barrier while preserving targeted protein degradation in cells beyond it.
PROTACs, or proteolysis-targeting chimeras, are designed to selectively remove disease-relevant proteins by redirecting the cell’s own protein degradation machinery. While this approach holds great therapeutic potential, getting PROTACs to their intended sites of action remains a major challenge. Biological barriers, such as those formed by endothelial cells, can strongly restrict the passage of therapeutic molecules into certain tissues.
To address this delivery bottleneck, the researchers developed liposomes functionalized with internalin B, a bacterial invasion protein derived from Listeria monocytogenes. During infection, the bacterium can traverse physiological barriers, while internalin B contributes to its ability to invade host cells. By repurposing this bacterial cell-entry mechanism, the team designed a biomimetic carrier to facilitate PROTAC transport across an endothelial barrier. InlB is known to participate in Listeria entry into mammalian cells.
In a human in vitro endothelial barrier model, the engineered liposomes enhanced trans-endothelial transport without compromising barrier integrity. The researchers further demonstrated that the system could transport the PROTAC MS4078 to neuroblastoma target cells located beyond the barrier.
Importantly, the delivered PROTAC remained functionally active: significant degradation of the target protein ALK was detected in downstream cells, an effect not observed with free MS4078 or non-functionalized liposomes.
The study therefore marks an important step toward overcoming a key delivery challenge in targeted protein degradation and demonstrates the potential of combining PROTAC technology with biomimetic nanomedicine and advanced in vitro models.
