Interview with Randy Schekman, PhD, UC Berkeley
Nobel Laureate
Drug Delivery, Endosomal Escape and the Search for New Fusogens
Professor of Molecular and Cell Biology, UC Berkeley | 2013 Nobel Laureate in Physiology or Medicine
Responses to interview questions from Tal Behar, Precision Medicine World Conference
Schekman's discoveries helped explain the machinery cells use to package and transport cargo. In this interview, he considers a central challenge for therapeutic delivery: ensuring that proteins and RNA reach the places inside a cell where they need to act.
Extracellular vesicles (EVs) are small, membrane-enclosed particles released by cells. Researchers are exploring them as delivery vehicles, but their cargo can remain trapped after a cell takes them up. Schekman discusses this barrier and how AI might help identify proteins that enable membrane fusion.
01
Cell Entry and Cargo Delivery: Why the distinction matters
A vesicle being taken up by a cell does not establish that its proteins or RNA reached the cytoplasm or nucleus. Schekman emphasizes the limited evidence for efficient delivery and the need to quantify what actually reaches those destinations.
The major misconception I see is the continued belief that extracellular vesicles deliver cargo proteins and RNA into the cytoplasm or nucleus. There is very little evidence for efficient delivery and where the efficiency has been properly quantified it is typically below 1%. The problem is that unlike enveloped viruses, EVs lack a membrane fusogen which would be required for the EV membrane to fuse at the cell surface or after internalization into an endosome.
Additional context from Schekman's PMWC talk abstract: He distinguishes ordinary EVs from EVs engineered to carry a viral or endogenous human fusogen, which he notes can deliver cargo efficiently.
02
Escaping the Endosome: The barrier beyond tissue targeting
For delivery beyond the liver, Schekman identifies escape from the endosome, a membrane-bound compartment inside the cell, as the hardest barrier.
Escaping the endosome as described in my answer to #1.
03
A Role for AI: Searching for new membrane-fusing proteins
A fusogen enables membranes to fuse. Schekman sees a possible role for AI in identifying previously unrecognized fusogens through their predicted structure, while the natural delivery process and the relevant protein remain to be established.
There may be specialized circumstances in which an endogenous fusogen is employed to deliver cargo from an EV. Such a dedicated process and the relevant fusogen remain to be identified. AI might help in detecting novel fusogens that are not homologous in sequence but possibly in predicted structure to known viral fusogens.
PMWC 2027 | JANUARY 28
Meet Randy Schekman at PMWC 2027
Randy Schekman will receive the PMWC 2027 Pioneer Award on Thursday, January 28, 2027.
- 9:00 AM Pioneer Award ceremony
