<p>Although sonodynamic therapy (SDT) is a promising cancer treatment that induces DNA and macromolecular damage through the generation of reactive oxygen species (ROS), its therapeutic efficacy is limited by local hypoxia and ROS defense mechanisms in tumors. This study proposed a novel tumor treatment approach, focusing on ROS-mediated therapy by targeting the nucleus and depleting glutathione (GSH) levels, which was achieved through a nanoplatform (Pt²⁺-CDs@PpIX) with integrated functions including GSH detection and depletion, pH-responsive drug release, and nuclear targeting. The Pt²⁺-CDs@PpIX nanoplatform effectively differentiated normal and cancer cells and also exhibited excellent biocompatibility. Depletion of GSH levels and increased ROS sensitivity of cells significantly improved the effectiveness of SDT, as demonstrated in vitro using Pt²⁺-CDs@PpIX, which also exhibited significant cellular uptake. Pt²⁺-CDs@PpIX exerted potent antitumor effects in both two-dimensional and three-dimensional tumor microenvironment models (3DM-7721). Moreover, in 3DM-7721 models, hepatoma cells (SMMC-7721) demonstrated significant inhibition of motility, invasion, and colony formation after exposure to Pt²⁺-CDs@PpIX. Furthermore, intravenous administration of the Pt²⁺-CDs@PpIX nanoplatform enabled precise and rapid tumor-targeting, followed by ultrasound-triggered therapy, without adverse effects in nude mice. Hence, this nanoplatform provides a promising strategy for designing cancer therapies and delivering nuclear-targeted drugs.</p>