Synchronized Phase-Transition-Induced Co-Assembly of Short Peptide and Dexmedetomidine for Efficient Drug Encapsulation and Slow Release.

Dexmedetomidine has been widely used clinically for perioperative sedation and analgesia, accompanied by the shortcomings of cardiovascular adverse effects and short duration. Although developing a slow-releasing dexmedetomidine formulation is a conventional strategy to address these problems, it is unfortunately limited by the small molecule and high solubility of the drug. In this study, we designed a self-assembling peptide (SAP) by referring to the chemical structure of dexmedetomidine, which contains a pH-responsive imidazole group and a hydrophobic benzene group. By also containing the two groups, the peptide could simultaneously undergo pH-induced phase-transition together with dexmedetomidine, leading to their co-assembly to form drug-peptide complexes. Different from well-ordered nanofibers formed by the peptide alone, the co-assembly system formed nanoparticles with relatively disordered core structures like biomolecular condensates. In this manner, the obtained formulation exhibited high drug encapsulation efficiency and a slow-releasing profile, which further alleviated hypotension and extended the duration of sedative and analgesic efficacy in animal models. This study proposed a promising strategy to design SAPs for drug delivery in a personalized way. It also provided the slow-releasing dexmedetomidine formulation as a promising candidate for clinical application.