Natural protein condensates respond to external stresses through stimuli-triggered multistage phase transitions. Reprogramming such transitions in synthetic systems is critical for rational design of self-adaptive materials with precisely regulated stimuli-responsiveness. Nevertheless, the sequence complexity of intrinsically disordered proteins (IDPs) and their competing assembly pathways often impede effective programing of multistage transitions in physiological conditions. Here, a class of short peptide synthons (Mw≈1500 Dalton) is synthesized by integrating intrinsically disordered and transiently ordered motifs derived from the low-complexity domain of IDPs. Remarkably, these peptide synthons exhibit thermoreversible quadruple phase transitions among monomers, self-coacervates, liquid crystals, and semi-crystallized solid gels. Mechanistic study reveals that the phase transitions are governed by two distinct assembly pathways, namely coacervation and fibrillization, which interact in both collaborative and competitive manners. Modifying the peptide sequence or molecular decorations allows for precise control over the phase transition temperatures, enabling sequential, multi-stage transitions to be activated by dose-dependent pathological cues (e.g., lactic acid) at the body temperature (37°C). These findings establish a highly versatile and programmable material platform to sequentially encode multistage phase behaviors into synthetic peptide assemblies, inspiring the development of next-generation disease biosensors, drug-delivery vehicles, and self-adaptive microrobots.
Xu et al. (Tue,) studied this question.