In Situ NADH-Activated BODIPY-Based Macrocyclic Supramolecular Photosensitizer for Chemo-Photodynamic Synergistic Tumor Therapy

Photodynamic therapy (PDT) based on supramolecular assembly has been receiving wide attention due to its great potential application in clinical treatment. Herein, we report a supramolecular photoelectron "reservoir" (SPR) constructed by tetracationic boron dipyrromethene (BODIPY)-based macrocycle (<b>BBox·</b>4Cl), doxorubicin (Dox), and tumor-targeted β-cyclodextrin-grafted hyaluronic acid (HACD). Upon irradiation, <b>BBox·</b>4Cl can in situ catalyze nicotinamide adenine dinucleotide (NADH) to continuously generate electrons to inject into SPR, which further transfers electrons to oxygen, inducing highly efficient hydroxyl radical generation even under hypoxia. Synergistically, Dox in SPR as "pump" can be encapsulated by <b>BBox·</b>4Cl and transport photoelectrons between two BODIPY units, while HACD as "sponge" can enrich <b>BBox·</b>4Cl by the electrostatic interaction to concentrate them closer in space, which facilitates intramolecular and intermolecular photoelectron transfer, respectively, and significantly enhances the generation of hydroxyl radicals. Meanwhile, electron replenishment in SPR causes NADH depletion and redox dysfunction, thereby accelerating the apoptosis and achieving highly effective synergistic tumor therapy.