Amphiphilic Pillar[5]arene-Based Pt(II)-Coordinated Dual-Cavity Metallacycle: Construction and Application in Enhanced Mitochondrial Photodynamic Cancer Therapy

Photodynamic therapy (PDT) has some major problems that seriously limit its use in treating tumors. For example, the photosensitizers tend to clump together, which causes fluorescence to drop sharply. They also do not produce enough singlet oxygen, and they cannot accurately reach the specific parts of cancer cells that need to be targeted. To address these bottlenecks, we designed and fabricated a new amphiphilic metallacycle based on pillar[5]arene and Pt(II), which we named AmMeCy. This material has a special two-cavity structure that has never been reported before. One cavity comes from the pillar[5]arene part and can precisely hold targeting molecules through host-guest interaction, The other cavity is formed by the Pt-coordinated metallacycle, which helps to confine the structure and control its functions. Notably, Pt coordination effectively restricts the π-π stacking of porphyrin moieties, fundamentally eliminating aggregation-caused quenching (ACQ) and significantly boosting fluorescence emission and 1O2 photogeneration efficiency. Benefiting from its amphiphilic nature, the metallacycle can spontaneously self-assemble into uniform nanostructures in aqueous media with excellent water dispersibility and biocompatibility. After host-guest encapsulation of mitochondrial-targeted guests, the assembled nanoparticles (AmMeCy ⊃ TPP NPs) achieve precise mitochondrial localization in tumor cells. Upon light irradiation, the amplified 1O2 burst efficiently triggers mitochondrial oxidative damage and tumor cell apoptosis. This work establishes a new dual-cavity supramolecular platform via metal-ligand coordination and pillararene host-guest chemistry, providing a facile and universal strategy for the structural optimization and functional upgrading of high-efficiency tumor PDT nanotherapeutics.