Oxygen-Gradient-Responsive Photosensitizing Gadolinium Phthalocyaninate for Self-Adaptive Type II/I Photodynamic Therapy Toward Heterogeneous Tumor Suppression.

The intrinsic spatial heterogeneity of oxygen within solid tumors remains a formidable barrier to photodynamic therapy (PDT). Traditional Type II photosensitizers are incapacitated by hypoxia, while oxygen-independent Type I agents are generally hindered by a kinetic bottleneck in reactive oxygen species (ROS) production that compromises therapeutic efficacy. To address these challenges, we propose an intelligent adaptive PDT strategy using hypoxia-responsive gadolinium phthalocyaninate nanophotosensitizers (Gd-N-mPEG NPs), capable of autonomously switching between Type II and Type I mechanisms in response to local oxygen gradients. In normoxic tumor peripheries, Gd-N-mPEG NPs facilitate efficient energy transfer (EnT) to generate singlet oxygen (1O2) via the Type II pathway. Upon deeper penetration into the tumor parenchyma, the NPs undergo azoreductase (AzoR)-mediated reduction in the hypoxic interior to convert into a hydrophobic derivative. Subsequent aggregation optimizes molecular stacking to facilitate enhanced interfacial electron transfer (ET), triggering a Type I response to effectively generate superoxide anions (O2·-). In vivo verification demonstrated that our intelligent NPs achieved a 95.6% inhibition rate in EMT-6 tumor-bearing mice. This work presents a strategy to address the heterogeneity of tumor oxygenation that overcomes conventional PDT limitations and establishes a foundational framework for designing next-generation photosensitizers.