Stimuli-Responsive Hydrogels from Liquid–Liquid Phase Separations of FUS-Derived Peptides

Defining soft biomaterials, including stimuli-responsive hydrogels, is essential for advancing applications such as targeted drug delivery, biosensing, and tissue engineering due to their ability to respond to environmental triggers dynamically. In this study, we characterized phase-separating peptides and elucidated the principles governing their self-assembly into hydrogels. Low-complexity aromatic-rich kinked segments (LARKS) were employed as building blocks to generate stimuli-responsive materials. By analyzing the properties of various multi-LARKS peptides, we developed a model informing the rational design of point mutations to modulate the mechanical properties and temperature stability of LARKS-based hydrogels, resulting in stimuli-responsive matrices. Our findings were further supported by demonstrating that these hydrogels effectively act as reservoir matrices capable of releasing drugs efficiently at 40 °C, highlighting their potential for biotechnological and medical applications.