Phase-tuned interfacial condensates drive transcellular access

Abstract

Nanocondensates occupy mesoscopic scale in both spatial scale and thermodynamic state, and the mesoscopic scale is central to structure-function conversion in living systems. However, how the dual mesoscopic properties of nanocondensates support biological function remains unclear because their small size and rapid dynamics hinder direct observation in living cells. Here we construct nanocondensates in situ at the cell-membrane interface and observe them permeating membranes within seconds, diffusing freely, exiting cells within minutes, re-entering neighbouring cells and traversing multilayered barriers. We report the first observation of this phenomenon and term it nanocondensate tunnelling. We find that nanocondensates cross membranes without membrane enclosure, preserving their wetting characteristics after passage. Theoretical and ultrastructural analyses support a transient-pore model linking this behaviour. We exploit nanocondensate tunnelling to transport small molecules, siRNA and antibodies across cellular barriers, and small molecules and siRNA across a multilayered corneal barrier, demonstrating its functional capacity for intercellular transfer. Our results suggest that nanocondensate tunnelling represents a previously undescribed mode of intercellular transfer. Nanocondensate tunnelling provides a physical basis for biologics delivery and a testable framework for investigating unresolved biological phenomena such as viral permeation.