Self-Assembly of Ru3-Aptamer Nanoparticles Triggers Pyroptosis through Photoredox Catalysis of NADH and Lysosomal Disruption

Photodynamic therapy (PDT) can induce tumor cell death. Ru3, a metal-based photosensitizer, features a high positive charge, a long triplet excited-state lifetime, and an excellent PDT activity. The aptamer AS1411, known for its ability to selectively bind to nucleolin (which is overexpressed in tumor cells), self-assembled with Ru3 into nanoparticles termed Ru3ApNPs. These nanoparticles specifically target SiHa tumor cells. Upon light irradiation, Ru3ApNPs increase intracellular ROS levels, catalyze NADH redox reactions, and induce lysosomal disruption, ultimately triggering pyroptosis in tumor cells. Notably, Ru3ApNPs demonstrate excellent tumor penetration in 3D multicellular spheroids (MCSs) of SiHa cells and effectively inhibit their growth under light exposure. Ru3ApNPs exhibit a mechanism of action distinct from that of traditional PDT. Furthermore, under light irradiation, Ru3ApNPs can effectively inhibit the growth of distant tumors and induce systemic immune responses in mice. Our data suggest that Ru3ApNPs can be developed as promising targeted therapeutic agents in the future.