Developing Type-I photosensitizers is considered as an efficient approach to overcome the deficiency of traditional photodynamic therapy(PDT) for hypoxic tumors.However,it remains ac hallenge to design photosensitizers for generating reactive oxygen species by the Type-I process.H erein, we report aseries of a,b-linked BODIPY dimers and atrimer that exclusively generate superoxider adical (O 2 À C)b yt he Type-I process upon light irradiation. The triplet formation originates from an effective excited-state relaxation from the initially populated singlet (S 1 )t ot riplet (T 1 )s tates via an intermediate triplet (T 2 )s tate.T he lowr eduction potential and ultralong lifetime of the T 1 state facilitate the efficient generation of O 2 À C by inter-molecular charge transfer to molecular oxygen. The energy gap of T 1 -S 0 is smaller than that between 3 O 2 and 1 O 2 therebyp recluding the generation of singlet oxygen by the Type-II process.T he trimer exhibits superior PDT performance under the hypoxic environment.

The highly oxygen-dependent nature of photodynamic therapy (PDT) limits its therapeutic efficacy against hypoxic solid tumors in clinics, which is an urgent problem to be solved. Herein, we develop an oxygen-independent supramolecular photodynamic agent that produces hydroxyl radical ( • OH) by oxidizing water in the presence of intracellularly abundant pyruvic acid under oxygen-free conditions. A fluorene-substituted BODIPY was designed as the electron donor and coassembled with perylene diimide as the electron acceptor to form the quadruple hydrogenbonded supramolecular photodynamic agent. Detailed mechanism studies reveal that intermolecular electron transfer and charge separation upon light irradiation result in an efficient generation of radical ion pairs. Under oxygen-free conditions, the cationic radicals directly oxidize water to generate highly cytotoxic • OH, and the anionic radicals transfer electrons to pyruvic acid, realizing the catalytic cycle. Thus, this photodynamic agent exhibited superb photocytotoxicity even under severe hypoxic environments and excellent in vivo antitumor efficacy on HeLa-bearing mouse models. This work provides a strategy for constructing oxygenindependent photodynamic agents, which opens up an avenue for effective PDT against hypoxic tumors.

Type-I photosensitizers (PSs) generate cytotoxic oxygen radicals by electron transfer even under hypoxic environments. Nevertheless, the preparation of Type-I PSs remains a challenge due to the competition of triplet-triplet energy...

Photosensitizer agents are essential for precise and efficient photodynamic therapy (PDT). However, most of the conventional photosensitizers still suffer from limitations such as aggregation-caused quenching (ACQ) in physiological environments and...

Given that Type-I photosensitizers (PSs) have hypoxia tolerance, developing general approaches to prepare Type-I PSs is of great importance, but remains a challenge. Here, we report a supramolecular strategy for the preparation of Type-I photodynamic agents, which simultaneously generate strong oxidizing cationic radicals and superoxide radicals, by introducing electron acceptors to the existing Type-II PSs. As a proof-of-concept, three electron acceptors were designed and co-assembled with a classical PS to produce quadruple hydrogen-bonded supramolecular photodynamic agents. The photo-induced electron transfer from the PS to the adjacent electron acceptor occurs efficiently, leading to the generation of a strong oxidizing PS+• and an anionic radical of the acceptor, which further transfers an electron to oxygen to form O2−•. In addition, these photodynamic agents induce direct photocatalytic oxidation of NADH with a turnover frequency as high as 53.7 min−1, which offers an oxygen-independent mechanism to damage tumors.