Supramolecular Dual Polypeptides Induced Tubulin Aggregation for Synergistic Cancer Theranostics

The advent of macrocycle-based supramolecular chemistry can offer powerful strategies for regulating vital bioactivities in living systems and bring about emerging technology in biomedical science. Herein, we construct a supra-biomacromolecular nanosystem involving microtubules, cell-permeable porphyrins, and antimitotic peptide-decorated permethyl-β-cyclodextrins for promoting cell apoptosis in a cooperative manner. Through specific polypeptide–tubulin recognition, cyclodextrin moieties are capable of anchoring to the tubulin surface and providing abundant hydrophobic microenvironments to accommodate the photosensitive porphyrins. Consequently, spherical tubulin aggregates are formed, and reactive oxygen species can be efficiently generated via the host–guest complexation. The combined usage of complexation-promoted photodynamic efficacy and tubulin aggregation gives more serious cell apoptosis under light irradiation in vitro and in vivo. To be envisioned, this supramolecularly enhanced photodynamic performance together with controlled aggregation of natural biomacromolecules may be developed as an innovative approach to improve the therapeutic potency against many diseases.基于大环的超分子化学（macrocycle-based supramolecular chemistry）的问世，可为调控生命系统中的关键生物活性提供强有力的策略，并为生物医学领域催生新兴技术。本研究中，我们构建了一种超生物大分子纳米系统，该系统包含微管（microtubules）、细胞可透过性卟啉（cell-permeable porphyrins）以及经抗有丝分裂肽修饰的全甲基β-环糊精（antimitotic peptide-decorated permethyl-β-cyclodextrins），以协同方式促进细胞凋亡（cell apoptosis）。通过特异性多肽-微管蛋白识别（polypeptide–tubulin recognition），环糊精基团能够锚定至微管蛋白表面，并提供丰富的疏水微环境以容纳光敏卟啉（photosensitive porphyrins）。由此形成球形微管蛋白聚集体（spherical tubulin aggregates），并可通过主客体络合（host–guest complexation）高效产生活性氧（reactive oxygen species）。络合促进的光动力疗效（photodynamic efficacy）与微管蛋白聚集的协同作用，可在体外与体内（in vitro and in vivo）的光辐照条件下引发更为显著的细胞凋亡。可以预见，这种超分子增强的光动力性能，结合天然生物大分子的可控聚集，有望发展为一种创新手段，以提升针对多种疾病的治疗效力。