Mitochondria‐to‐Nucleus Trafficking NIR‐II Type I AIE Photosensitizer Synergistically Activates cGAS‐STING Pathway for Efficient Tumor Eradication

Abstract Activating the cGAS–STING signaling axis has emerged as a promising therapeutic strategy for combating tumor proliferation. However, conventional cGAS–STING agonists are hindered by the lack of precision in organelle targeting and limited capacity to induce DNA damage, impeding their therapeutic efficacy. Herein, it is developed a mitochondria‐to‐nucleus trafficking near‐infrared II (NIR‐II) type I photosensitizer (MPTB) for the synergistic activation of the cGAS‐STING pathway. The incorporation of the N,N‐dimethylamino tetraphenylethene substituent, an electron‐donating moiety with conformational distortion, finely tuned the radiative and non‐radiative decay of MPTB, endowing it with exceptional NIR‐II emission properties, robust type I reactive oxygen species (ROS) generation capacity, and remarkable photothermal conversion efficiency (63.6%). The lipocationic nature of MPTB facilitated its precise accumulation in mitochondria. Upon irradiation with 635 nm laser, MPTB‐mediated phototherapy caused damage to mitochondrial DNA (mtDNA). Subsequently, MPTB translocated to the nucleus, resulting in the impairment of nuclear DNA (nDNA). This synergistic mtDNA and nDNA damage led to an increased release of DNA fragments, which efficiently activated the cGAS‐STING signaling pathway and triggered immunogenic cell death, thereby enhancing the therapeutic efficacy. The formulated MPTB nanoparticles demonstrated intense NIR‐II fluorescence/photothermal imaging capabilities in vivo, enabling precise imaging‐guided phototherapy to suppress tumor proliferation with minimal off‐target effects.