Phytic Acid-Based Nanoplatform Mediates Reinforcement of Cuproptosis Induction and Pathway Inhibition.

Cuproptosis has emerged as a distinctive form of regulated cell death with promising anticancer potential, yet its efficacy is constrained by copper-triggered activation of oncogenic PI3K/AKT/mTOR signaling. Here, we present a bioinspired nanoparticle platform that integrates cuproptosis induction with simultaneous oncogenic pathway suppression. Specifically, copper ions serve as cationic bridges to assemble phytic acid (PA) and transferrin (Tf) into ternary PA-Cu-Tf nanoparticles (PCT NPs), achieving a unique synergy between chemical coordination and biological targeting. Leveraging Tf-mediated tumor targeting, PCT NPs selectively accumulate within tumors, triggering intracellular copper overload and robust cuproptosis. Remarkably, PA not only acts as a copper chelator but also suppresses PI3K/AKT/mTOR hyperactivation, thereby abrogating compensatory survival signaling and amplifying cuproptosis. Moreover, PCT NPs-induced cuproptosis triggers immunogenic cell death, promotes dendritic cell maturation, and enhances intratumoral immune infiltration, eliciting a robust systemic antitumor response. This work demonstrates the precise integration of cuproptosis induction with concurrent oncogenic signaling inhibition, establishing a therapeutic paradigm with significant translational potential for cancer treatment.