Biomolecular condensates, dynamic membraneless organelles formed via liquid-liquid phase separation (LLPS), are reshaping our understanding of cellular organization. These compartments concentrate specific molecules to orchestrate vital processes, from transcription to stress response. However, this functional dynamism is shadowed by a critical vulnerability: the transition from a fluid, functional state to a solid, often pathological, aggregate. This "aging" process is a hallmark of devastating neurodegenerative diseases like ALS and Huntington's, yet the precise molecular triggers that drive this liquid-to-solid transition within the cell's complex environment have remained a central enigma in the field [2, 3].
Early research established the principles of LLPS and revealed that condensates are not static but can mature over time, with RNA emerging as a key modulator of their material properties [4]. However, a crucial gap in knowledge persisted: how do specific, disease-associated RNA sequences hijack this process to initiate solidification within an already complex, multi-component condensate? Answering this required moving beyond simple systems to dissect the competitive interactions at the heart of condensate aging.
A landmark 2025 study in Nature Chemistry by Mahendran, Wadsworth, and Banerjee provides a decisive answer, revealing a fundamental mechanism of condensate aging driven by homotypic RNA interactions [1]. The research elegantly dissects how pathogenic RNAs can trigger a liquid-to-solid transition by forming their own distinct, solid phase inside a host condensate.
To isolate the behavior of a specific RNA, the researchers constructed a stable, liquid-like model condensate using a multivalent arginine-glycine-glycine (RGG) polypeptide and a poly-thymine DNA scaffold. Into this homogenous liquid, they introduced a "client" RNA known to form stable G-quadruplex structures—the telomeric repeat-containing RNA (TERRA).
The results were striking. While initially dispersed, the TERRA molecules underwent a time-dependent self-assembly, forming distinct, solid-like clusters within the core of the host condensate. This process created a multiphasic structure: a dense, immobile RNA core surrounded by a fluid, RNA-depleted shell. This was not simple precipitation but a "phase-within-a-phase" transition, driven by the RNA's intrinsic properties.
The study meticulously deciphers the rules governing this phenomenon:
Crucially, the research demonstrates that this pathological transition is not irreversible. The introduction of antisense oligonucleotides (ASOs) that specifically bind to the TERRA sequence successfully dissolved the pre-formed RNA clusters. Furthermore, the RNA-binding protein G3BP1 was found to act as a natural "chaperone," preventing or significantly delaying RNA clustering by introducing competing, heterotypic interactions. This suggests that cells possess intrinsic mechanisms to maintain condensate fluidity, which can be overwhelmed in disease states.
This study represents a paradigm shift, moving the field from a general understanding of condensate aging to a specific, quantitative mechanism centered on RNA percolation. It reframes pathological aggregation not as a simple protein-centric event but as a complex, multi-component process where RNA can act as a primary driver. The findings provide a physical basis for the "activation energy barrier" that separates functional liquidity from pathological solidity, determined by RNA sequence, structure, and length [5].
The discovery that ASOs and RBPs can counteract this process opens exciting therapeutic avenues [6]. Instead of targeting downstream aggregates, future therapies could aim to prevent the initial percolation event, either by disrupting homotypic RNA interactions or by bolstering the cell's natural chaperone systems.
However, significant challenges remain. The next frontier is to understand how the full complexity of the cellular milieu—including molecular crowding, ATP-driven reactions, and a diverse cast of other proteins and RNAs—modulates these transitions. Systematically mapping the vast sequence-and-structure space of RNAs that promote or inhibit percolation is a monumental task that requires a new scale of experimentation. Reconstituting these complex systems in vitro requires high-purity components, a bottleneck that novel purification methods like organelle-based sorting aim to address. To accelerate discovery, platforms that enable massive-scale screening and data generation, such as Ailurus vec's self-selecting expression libraries, could be instrumental in building the predictive, AI-driven models needed to design next-generation RNA therapeutics.
In conclusion, Mahendran and colleagues have provided a powerful framework for understanding how pathogenic RNAs hijack biomolecular condensates. By elucidating the principles of RNA percolation, their work not only decodes a fundamental mechanism of cellular aging and disease but also illuminates a clear and promising path toward therapeutic intervention [1, 7].
Ailurus Bio is a pioneering company building bioprograms, which are genetic codes that act as living software to instruct biology. We develop foundational DNAs and libraries to turn lab-grown cells into living instruments that streamline complex procedures in biological research and production. We offer these bioprograms to scientists and developers worldwide, empowering a diverse spectrum of scientific discovery and applications. Our mission is to make biology a general-purpose technology, as easy to use and accessible as modern computers, by constructing a biocomputer architecture for all.
