Dissecting Rate-Limiting Processes in Biomolecular Condensate Exchange Dynamics

The speed with which biomolecular condensates exchange components with their environment can influence how fast biochemical reactions occur inside them and how fast they respond to environmental changes, thereby directly impacting their function. While FRAP experiments are routinely performed to measure this exchange timescale, it is challenging to distinguish the various physical processes limiting FRAP recovery and their timescales. Here, we present a reaction-diffusion model for condensate exchange dynamics and show that such exchange can differ from that of conventional liquid droplets due to the presence of a percolated network, which gives rise to different mobilities in the dense phase. In our model, exchange can be limited by dense-phase diffusion of either the high- or low-mobility species, dilute-phase diffusion, or attachment/detachment of molecules to/from the network at the surface or throughout the condensate bulk. Through analytic derivations and numerical simulations, we quantify the contributions of these distinct processes to the overall exchange timescale and predict a testable relationship between the exchange timescale and condensate size. We discover that the exchange dynamics can be accelerated via a pathway in which molecules pass through the meshwork pores and attach/detach directly in the condensate interior. Notably, this pathway leads to a new regime in which the exchange timescale becomes independent of droplet size, which we validate through FRAP experiments on DNA nanostars. Our work offers insight into the predominant physical mechanisms driving condensate material exchange, with implications for natural and engineered systems.