Stimuli-controlled peptide self-assembly with secondary structure transitions and its application in drug release

Short peptides can self-assemble into supramolecular materials and be used for promising biomedical applications. This area of research has seen tremendous development in recent years. However, the preparation of nanofibers with a predefined secondary structure through rational design remains a challenge. Herein, a peptide-based building block, Fmoc-KKYpYp-COOH (P1), was rationally designed for dual-triggered self-assembly by pH and enzyme for the first time. By delicately modulating the surface charges of the peptides using different triggers, i.e. pH or enzyme, we have designed peptides that are capable of self-assembling into nanoscale structures with distinct secondary structures. Upon ALP treatment, precursor P1 was efficiently transformed into a hydrogelator, Fmoc-KKYY-COOH (P2), and self-assembled to nanofibers with a partial alpha-helix structure. In contrast, P1 displays a typical fibrous network structure with a predominant beta-sheet arrangement upon pH stimulus. Furthermore, P1 was successfully used to co-assemble with a prodrug under ALP catalysis without compromising the anti-cancer activity of the drug. The combination index (CI) values indicated a synergistic effect between P1 and Ep. We envision that this study will provide a powerful approach for rationally designing peptide nanofibers with a predefined secondary structure in the future.