Host-Guest Interaction-Instructed In Situ Self-Assembly of Therapeutic Peptides for Enhancing Antitumor Efficacy

Therapeutic peptides have played a huge role in chemotherapy due to their excellent biological activity and biocompatibility. However, therapeutic peptides are vulnerable to enzymatic digestion, which makes them with fast elimination in vivo. Nowadays, peptides self-assembly has become a powerful strategy for constructing nanostructures to boost their stability and bioactivity in vivo. To our knowledge, host-guest interaction-instructed in situ peptides self-assembly for biomedical applications is still rare. Herein, we intended to develop a supramolecular complex (CB[7]-FFYSV) based on the host-guest interactions between cucurbit[7]uril (CB[7]) and N-terminal aromatic residues of a therapeutic peptide (Phe-Phe-Tyr-Ser-Val, FFYSV). CB[7]-FFYSV can release therapeutic peptide FFYSV under the competition of endogenous tumor biomarker spermine (SPM) and then FFYSV can self-assemble in situ with the formation of nanofibers for enhancing tumor treatment. CB[7]-YSV without the self-assembly ability is the control group. The stability of FFYSV was obviously improved under proteinase K after encapsulation by CB[7]. CB[7]-YSV or CB[7]-FFYSV exhibited more significant toxicity to A549 and 4T1 cells with high expression of SPM than YSV or FFYSV. CB[7]-FFYSV is more effective than CB[7]-YSV due to the self-assembly of FFYSV with the formation of dense short nanofibers with an average width of 38.5 ± 12.4 nm and a length of 431.5 ± 63.1 nm in the cytoplasm. However, YSV or FFYSV displayed obvious toxicity while CB[7]-YSV or CB[7]-FFYSV exhibited negligible toxicity to HepG2 cells with low expression of SPM. Furthermore, the SPM-instructed release and subsequent in situ self-assembly of FFYSV enhanced antitumor efficacy of YSV in vivo. We envision that the host-guest interaction-instructed in situ self-assembly will be useful for effective treatment of diseases in the future.