AIE Photosensitizer‐Mediated Photodegradation of Carbonic Anhydrase IX Triggers Ferroptosis

ABSTRACT To address hypoxia‐driven therapeutic resistance exacerbated by photodynamic therapy (PDT), targeted photodegradation of hypoxia‐inducible carbonic anhydrase IX (CAIX), an enzyme overexpressed on the tumor cell membrane, offers a direct countermeasure. Toward this goal, TBC was designed and synthesized as an aggregation‐induced emission photosensitizer (AIE PS) featuring a benzenesulfonamide tail for specifical CAIX targeting. Compared with the aniline‐modified TBN , the substitution with benzenesulfonamide endowed TBC with enhanced charge‐transfer characteristics, a more pronounced AIE effect, red‐shifted emission, and superior Type I/II PDT efficacy. TBC acted through selective CAIX binding and inhibition, an effect markedly amplified by its subsequent photodegradation, thereby promoting tumor‐specific accumulation while simultaneously alleviating hypoxia. Mechanistically, CAIX photodegradation synergistically mitigated hypoxia and induced intracellular acidosis, leading to elevated reactive oxygen species levels and lipid peroxidation that drove robust ferroptosis. Furthermore, TBC induced a spatiotemporal targeting cascade from the cell membrane to the Golgi apparatus and endoplasmic reticulum. The light‐induced stress at these sites potentiated ferroptosis and stimulated antitumor immunity. To our knowledge, this is the first AIE PS enabling in situ CAIX photodegradation to trigger ferroptosis via dual hypoxia alleviation and intracellular acidosis, offering a novel strategy against PDT resistance.