Decoding Biomolecular Phase Separation: From Physiological Roles to Pathological Mechanisms and Therapeutic Biomaterials Design

Abstract

ABSTRACT Biomolecular phase separation (BPS), encompassing liquid‐liquid, liquid‐gel, and liquid‐solid transitions, has emerged as a fundamental principle governing cellular organization and function. Dysregulation of these phase states acts as a pathogenic driver of diverse intractable diseases, including neurodegeneration, cancer, and autoimmune disorders. The intrinsic properties of biomolecular condensates, self‐assembly, dynamic reversibility, and environmental responsiveness, also offer a robust blueprint for next‐generation biomaterial design. Despite rapid progress across the field, a cohesive framework linking phase transition physics, pathological mechanisms, and translational engineering remains absent. Here, we delineate the full continuum of liquid‐liquid, liquid‐gel and liquid‐solid phase separation, elucidating how dynamic interconversion across phase states regulates core physiological processes and drives the pathogenesis of neurodegeneration, cancer and autoimmune disorders. Meanwhile, we establish a property‐design‐function paradigm that translates the physicochemical rules of phase separation into rational biomaterial engineering. Building on this mechanistic foundation, we systematically evaluate emerging therapeutic strategies that target aberrant condensates via either BPS induction or inhibition. We also highlight BPS‐inspired biomaterials across cell‐mimetic systems, responsive drug delivery platforms, bioactive scaffolds, and high‐performance imaging probes. Key translational challenges and forward‐looking pathways are discussed alongside these advances. This review provides an integrated cross‐disciplinary perspective bridging physicochemical fundamentals, pathological implications, and biomedical engineering.