Near-infrared photosensitizers adaptive to tumor hypoxic microenvironment for synergistic photothermal-photodynamic and immunotherapy

For photodynamic therapy (PDT), traditional type II photosensitizers rely on local molecular oxygen to produce highly cytotoxic singlet oxygen (1O2) to kill tumor cells, which is severely restricted by the hypoxic tumor microenvironment (TME). We herein develop a heavy-metal-free and near-infrared (NIR) photosensitizer BTAC6 and its hydrophilic nanoparticles (BTAC6 NPs) with enhanced tumor-killing effects in both normoxic and hypoxic TME via synergistic photothermal therapy (PTT), PDT (both type I and II) and immunotherapy. BTAC6 possesses donor-acceptor alternating structure (A-DA'D-A) and large-conjugated skeleton, contributing to superb NIR light absorption, narrowed energy gap (Delta EST) and enhanced intersystem crossing (ISC) process for superior PTT and PDT performances. Under the stimulation of 808 nm NIR laser, BTAC6 NPs can adapt to both normoxic and hypoxic TME to effectively ablate tumors. It presents synergistic type II PDT/PTT to generate topical heat and 1O2 in normoxia, and exhibits type I PDT/PTT to produce hyperpyrexia, highly-reactive hydroxyl radical (center dot OH) and superoxide anion (O2 center dot-) in hypoxia, achieving an over 98 % tumor inhibition rate in mice. Importantly, this synergistic PDT/PTT treatment can activate a durable anti-tumor immune response while destroying the tumors. This work provides a molecular structure design strategy of developing heavy-metal-free NIR photosensitizers to conquer hypoxia.