Programmable macromolecule delivery via engineered trogocytosis.

Area of Science:

• Cell Biology
• Biotechnology
• Molecular Engineering

Background:

• Trogocytosis, the transfer of plasma membrane fragments during cell-cell contact, presents opportunities for macromolecular delivery.
• Current limitations include uncertain cargo fate, restriction to membrane components, and unclear applicability across cell types.

Purpose of the Study:

• To engineer cells for efficient and functional protein transfer to recipient cells via trogocytosis.
• To establish key principles for enhancing trogocytosis-mediated delivery.
• To develop a versatile and programmable cell-based delivery system.

Main Methods:

• Engineering donor cells with designed receptors for specific surface ligand recognition.
• Implementing pH-responsive membrane fusion and inducible cargo localization/release mechanisms.
• Investigating dynamin- and endosome acidification-dependent pathways for cargo transfer.

Main Results:

• Demonstrated successful protein transfer between engineered cells through direct contact.
• Identified engineering principles that enhance transfer efficiency and cargo functionalization.
• Developed TRANSFER, a versatile system with programmable cell specificity and tunability.
• Showcased TRANSFER's ability to deliver large therapeutic proteins and mediate genome editing.

Conclusions:

• Trogocytosis can be engineered into a programmable and versatile framework for cell-based macromolecular delivery.
• The TRANSFER system offers broad applicability across diverse cell types.
• This approach enables precise control over cargo delivery and therapeutic applications.