Biomolecular condensates play crucial roles in cellular organization and are emerging as versatile platforms for biomedicine. However, their limited pH stability constrains functionality across diverse physiological environments. Here, we report a molecular shielding strategy to achieve tunable coacervation of simple amino acids over a wide pH range (1.0-13.0). To be specific, selective modification of terminal ionizable groups blocks pH-induced charge variations, thereby leading to phase behavior independent of environmental pH. In addition, such amino acid-based coacervates possess distinct thermoresponsive features, displaying either elastin-like lower critical solution temperature (LCST) or prion-like upper critical solution temperature (UCST) phase transitions. In particular, the programmable pH-responsive feature permits biocompatible N-terminal shielding phenylalanine coacervates to remain stable under harsh gastric conditions and prolonged gastrointestinal drug retention. As a result, highly efficient oral delivery and therapy in acute colitis are achieved in vivo. This work opens a new avenue to construct programmable coacervates responding to physiological environmental changes for biomedical applications.
Yu et al. (2026) studied this question.