Mitochondria-targeted tertiary amine N-Oxide nanoparticles with photosensitizer conjugation for photopyroptotic cancer therapy

Abstract Although photodynamic therapy has emerged as a promising strategy for cancer treatment, its efficacy is often restricted by the extremely short diffusion radius of reactive oxygen species (ROS). Concentrating ROS generation within vulnerable organelles, such as mitochondria, represents an effective avenue to overcome the limited immunogenicity often associated with conventional apoptosis and amplify photodynamic damage. To address this challenge, this study introduces a zwitterionic polymer, poly(2-(N-oxide-dimethylamino)ethyl methacrylate) (OPDMA), featuring a tertiary amine N-oxide (TANO) structure. To evaluate its therapeutic potential, the model photosensitizer pyropheophorbide-a (Ppa) was chemically conjugated to the OPDMA matrix, enabling its self-assembly into OPDMA-Ppa nanoparticles. This design endows the nanoparticles with favorable hydration and colloidal stability, thereby contributing directly to an extended blood circulation. Notably, without relying on traditional, potentially cytotoxic cationic ligands, this material achieves subcellular localization to mitochondria, thereby facilitating the mitochondrial targeting of the conjugated photosensitizer. Under 660 nm laser irradiation, the nanoparticles successfully trigger a localized oxidative burst and the collapse of mitochondrial membrane potential. This organelle dysfunction subsequently activates the classical caspase-1/gasdermin D-mediated pyroptotic pathway, accompanied by characteristic cellular swelling and the release of cellular contents. In an EMT6 tumor-bearing mouse model, the OPDMA-Ppa nanoparticles achieved a final tumor inhibition rate of 80.0%. Overall, this work provides a promising approach for designing organelle-specific nanoparticles to enhance photopyroptosis-mediated cancer therapy.