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

ABSTRACT

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 ( ¹ O ₂ ) 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 (O ₂ · ⁻ ). 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.