Spatiotemporal Regulation of Cell Fate in Living Systems Using Photoactivatable Artificial DNA Membraneless Organelles

TL;DR

Researchers created synthetic DNA-based membraneless organelles that can control cell fate with spatiotemporal precision in living systems.

Contribution

A self-stabilizing DNA membraneless organelle is developed for precise spatiotemporal regulation of cell fate in complex physiological systems.

Findings

DNA coacervates assembled via phase separation enable self-stabilization and function encoding.

Photoactivatable DNA membraneless organelles were used to manage cancer in a mouse model.

The method avoids surface coating or hybridization, maintaining molecular communication properties.

Abstract

Coacervates formed
by liquid–liquid phase separation emerge
as important biomimetic models for studying the dynamic behaviors
of membraneless organelles and synchronously motivating the creation
of smart architectures with the regulation of cell fate. Despite continuous
progress, it remains challenging to balance the trade-offs among structural
stability, versatility, and molecular communication for regulation
of cell fate and systemic investigation in a complex physiological
system. Herein, we present a self-stabilizing and fastener-bound gain-of-function
methodology to create a new type of synthetic DNA membraneless organelle
(MO) with high stability and controlled bioactivity on the basis of
DNA coacervates. Specifically, long single-strand DNA generated by
rolling circle amplification (RCA) is selected as the scaffold that
assembles into membraneless coacervates via phase separation. Intriguingly,
the as-formed DNA MO can recruit RCA byproducts and other components
to achieve self-stabilization, nanoscale condensation, and function
encoding. As a proof of concept, photoactivatable DNA MO is constructed
and successfully employed for time-dependent accumulation and spatiotemporal
management of cancer in a mouse model. This study offers new, important
insights into synthetic membraneless organelles for the basic understanding
and manipulation of important life processes.

Coacervate membraneless organelles formed through liquid−liquid
phase separation (LLPS) have been actively investigated as an emerging
cargo delivery platform to harbor proteins, RNAs, and therapeutic
molecules. However, a trade-off among structural stability, versatility,
and molecular communication in physiological conditions hampers their
application for systemic administration. Our study develops self-stabilizing
and fastener-bound gain-of-function DNA membraneless organelles (MOs).
Unlike traditional approaches to obtain functional MOs via complicated
surface coating or hybridization, long single-strand DNA coacervates
are used as scaffolds, enabling self-stabilization and function encoding
by simply recruiting surrounding components during LLPS for systematic
regulation of cell fate, without loss of communication properties.

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