Dysregulation of liquid-liquid phase separation: from molecular mechanisms to targeted therapies in cardiovascular diseases.

Liquid-liquid phase separation (LLPS), a fundamental biological process that drives the formation of membraneless organelles (MLOs) through non-covalent interactions, has emerged as a central regulatory mechanism in cellular physiology and stress responses. Increasing evidence links dysregulated LLPS to the pathogenesis of cardiovascular diseases (CVDs). However, the conserved molecular mechanisms underlying LLPS dysfunction across diverse CVDs, as well as the translation of LLPS-targeted strategies into clinical applications, remain poorly understood. In this review, we propose a novel hypothetical framework in which m6A modification-mediated RNA-intrinsically disordered protein (IDP) LLPS may serve as a conserved regulatory axis in CVDs, integrating the pathological mechanisms of multiple disease contexts. We further highlight that the irreversible transition of biomolecular condensates (BCs) from liquid to gel/solid states serves as a key driver of pathological irreversibility in end-stage CVDs, and demonstrate that m6A RNA modification and protein post-translational modifications (PTMs) act synergistically to regulate the RNA-IDP LLPS axis. Additionally, we summarize four emerging LLPS-targeted therapeutic strategies, including small-molecule modulators, biomaterial-based delivery systems, chiral nanomaterial interventions, and PTM-focused modulation. By connecting molecular mechanisms, disease relevance, and therapeutic potential, this review emphasizes the m6A-RNA-IDP axis and irreversible BC transitions as promising targets for broad-spectrum CVD intervention, providing a comprehensive framework to advance both basic research and translational nanobiotechnology applications.