Title: Programmable Macromolecule Delivery via Engineered Trogocytosis

Abstract: Cell type-specific delivery remains a critical bottleneck in realizing the full potential of macromolecule-based therapies for the treatment of various diseases. Traditional delivery systems, such as viral vectors and nanoparticles, often suffer from restricted cargo capacity, poor cell type specificity, and an inability to react to external cues or in vivo microenvironments. Cells are the fundamental units of human body and can produce large biomolecular cargos, migrate to target tissues, and process diverse surface ligands or external cues. They can be readily engineered to express desired cargos and recognize specific cell types, enhancing their potential as a powerful platform for targeted therapeutic delivery. However, we still lack a platform to engineer cell-to-cell macromolecule transfer in a programmable manner to enable living cell-based, cell type-specific delivery.

Inspired by trogocytosis, in which plasma membrane patch and associated molecules of one cell are acquired by another through direct cell-cell contact, we demonstrated that donor cells equipped with engineered receptors can efficiently deliver molecular cargos to recipient cells expressing specific surface ligands. We showed that by co-transferring pH-sensitive membrane fusion protein (termed fusogen), the trogocytosed cargo can efficiently escape the endosome, self-cleave through a pH-sensitive release domain, and translocate to the cytosol or nucleus to perform its function. Exploiting these findings, we developed a cell-based delivery platform termed trogocytosis-inspired transfer and functional effector release (TRANSFER). We systematically characterized the mechanism of TRANSFER, including its dependence on the dynamin pathway and endosomal acidification. Our study establishes engineered trogocytosis as a programmable, versatile framework for cell-based macromolecular delivery, with the potential to be further developed into a therapeutically relevant delivery system in vivo.

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