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

Photodynamic therapy (PDT) can induce tumor cell death. <b>Ru3</b>, 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 <b>Ru3</b> into nanoparticles termed <b>Ru3ApNPs</b>. These nanoparticles specifically target SiHa tumor cells. Upon light irradiation, <b>Ru3ApNPs</b> increase intracellular ROS levels, catalyze NADH redox reactions, and induce lysosomal disruption, ultimately triggering pyroptosis in tumor cells. Notably, <b>Ru3ApNPs</b> demonstrate excellent tumor penetration in 3D multicellular spheroids (MCSs) of SiHa cells and effectively inhibit their growth under light exposure. <b>Ru3ApNPs</b> exhibit a mechanism of action distinct from that of traditional PDT. Furthermore, under light irradiation, <b>Ru3ApNPs</b> can effectively inhibit the growth of distant tumors and induce systemic immune responses in mice. Our data suggest that <b>Ru3ApNPs</b> can be developed as promising targeted therapeutic agents in the future.