Amino Acid-based Coacervates with Tunable Stimulus-Responsive Properties for Enhanced Acute Colitis Therapy

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.