Bone-Penetrating Copper-Coordinated Nanoassembly Elicits Cuproptosis for Multimodal Cancer Therapy

Copper-based nanotherapeutics have emerged as a promising anticancer platform by simultaneously inducing cuproptosis and enabling multimodal therapy. However, their clinical application remains constrained by uncontrolled copper ion release, a complex tumor microenvironment (TME), and insufficient therapeutic penetration. To address these challenges, we developed a multifunctional nanoplatform (BCB) through the integration of baicalein-copper coordinated nanoparticles with a boron-dipyrromethene-derived photosensitizer. BCB exhibited a uniform spherical morphology with an average size of approximately 150 nm, excellent stability, TME-responsive release, and multiple catalytic functions, including peroxidase-like and photodynamic activities. Through synergistic chemodynamic and phototherapeutic actions, BCB effectively depleted glutathione, generated abundant reactive oxygen species, disrupted mitochondrial membrane potential, and triggered cuproptosis. In murine melanoma models, BCB plus light irradiation achieved a 75% cure rate, even at low doses. Moreover, BCB exhibited antimigratory properties and bone-penetrating capability, with selective accumulation in intramedullary tumor sites, highlighting its potential for treating bone-metastatic cancers. This multimodal nanoplatform represents a promising synergistic strategy for overcoming current therapeutic limitations in both primary and metastatic tumors.