Design of a Wobble‐Scheme Heterojunction for Catalytic Cancer Therapy

ABSTRACT Nanocatalytic medicine has emerged as a promising strategy for tumor therapy, where the rational design of photocatalytic nanoscale heterostructures plays a pivotal role. Herein, an organic–inorganic core–shell nanoreactor (Bi@COF) is designed as a wobble‐scheme heterojunction with responsiveness to the tumor microenvironment (TME). In the acidic TME, the COF shell undergoes reversible enolimine‐ketoenamine tautomerization, enabling dynamic switching between reduction/oxidation (RP/OP) junctions. Under near‐infrared irradiation (NIR), the reconfigured heterojunction efficiently catalyzes in situ H 2 O 2 generation, while the photothermal effect further promotes its decomposition into hydroxyl radicals (·OH). This process establishes an intracellular self‐sufficient reactive oxygen species (ROS) system for synergistic photothermal and photodynamic tumor therapy. Experimental and theoretical analyses demonstrate that COF tautomerization reconstructs the conjugated framework, modulates band alignment, and reverses the type of RP/OP junction. Structurally, the dual donor–acceptor (D‐C = N‐A) structure of COF‐H facilitates charge transfer, while protonated imine groups provide active sites for proton transfer. These features synergistically promote proton‐coupled electron transfer (PCET) under acidic TME conditions, thereby lowering the catalytic energy barrier and facilitating the generation of H 2 O 2 . In this work, the wobble‐scheme heterojunction‐mediated ROS self‐supply system disrupts intracellular redox homeostasis and induces cancer cell apoptosis, offering a promising paradigm for integrating dynamically regulated heterojunctions with nanocatalytic medicine.