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

ABSTRACT

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.