Supramolecular Aggregation-Induced Emission Photosensitizer Encapsulated by Cucurbit[8]uril Nanocavity Boosts Hypoxia-Activated Tumor Therapy

The limited efficacy of chemotherapy induced by the hypoxic tumor microenvironment remains a major obstacle in clinical oncology. To address this, we designed and synthesized a series of aggregation-induced emission photosensitizers with donor-π-acceptor structures, exemplified by SC-3. Upon assembly with cucurbit[8]-uril (CB[8]), the nanosupramolecular photosensitizer 2SC-3/CB[8] significantly enhanced singlet oxygen (¹O₂) generation and exacerbated cellular hypoxia. When coadministered with the hypoxia-activated chemotherapeutic tirapazamine (TPZ), we found that 2SC-3/CB[8] further amplified TPZ's antitumor efficacy in MDA-MB-231 breast cancer cells. Experimental studies and density functional theory calculations confirmed that SC-3 exhibits potent photodynamic therapy activity with high mitochondrial specificity. In addition, we found that CB[8]-induced depletion of intracellular spermine further contributed to the death of the tumor cells. Together, these findings highlight the potential of combining supramolecular photosensitizers with hypoxia-activated chemotherapy as a promising and synergistic strategy for the treatment of solid tumors.