Type I Rhodamine-Sensitized Iridium(III) Complex Photosensitizers Activate Pyroptosis for Hypoxic Photodynamic Immunotherapy

Developing hypoxia-tolerant type I photosensitizers (PSs) that induce pyroptosis offers an attractive approach to address the poor efficacy of photodynamic immunotherapy (PDI), which is commonly compromised by hypoxia and immune suppression in the tumor microenvironment. However, rational design of efficient type I PSs remains challenging due to the limited understanding of their structure–property relationship. Herein, we synthesize a series of cyclometalated Ir(III) complexes (Ir1–Ir5) with an acetylacetone-functionalized rhodamine ligand using a donor–acceptor (D–A) strategy, where the Ir(III) moiety and rhodamine ligands act as the electron donor and acceptor, respectively. By the introduction of an acetylacetone anchoring group, intramolecular photoinduced electron transfer is promoted through the modulation of the energy level of the Ir(III)-excited state. Their ability to generate superoxide radicals under low-power white light was significantly improved, achieving efficiency 20-fold higher than that of methylene blue. Remarkably, Ir3 exhibits exceptional phototoxicity under hypoxia (IC₅₀ = 0.46 μM) due to enhanced radical production. In vitro/vivo studies confirm that Ir3 could activate pyroptosis in CT26 cells, triggering a strong immune response and effectively ablating tumors. This work demonstrates that switching type-II to type I PSs is achieved from the enhanced intramolecular electron transfer through the modification of the anchoring group, providing a promising example for hypoxia-resistant PDI.