Synergistic Induction of Calcium Overload and ROS Burst by a Core-Shell Nanoparticle for Potentiated Tumor Suppression in Breast Cancer

To exploit the therapeutic synergy of nanoparticle-induced calcium overload and oxidative stress dysregulation, we developed a core-shell nanoplatform, termed CK@PTM (comprising kaempferol-loaded calcium peroxide nanoparticles coated with a PEG-tannic acid/manganese metal-phenolic network), to amplified therapeutic efficacy against breast cancer. Structurally, kaempferol (KAE)-loaded calcium peroxide (CaO₂) nanoparticles served as the functional core, subsequently enveloped by a dual-responsive metal-phenolic network (MPN) formed through Mn²⁺coordination with polyethylene glycol-modified tannic acid (PEG-TA). This hierarchical architecture enabled pH/glutathione (GSH) dual-responsive payload co-release,​​ facilitated by acid-triggered CaO₂ dissolution concurrent with pH/GSH- triggered MPN decomposition. Critically, CK@PTM orchestrated a severe redox imbalance via concomitant GSH depletion and reactive oxygen species (ROS) burst, thereby amplifying tumoricidal activity.​​ Cellular uptake assays revealed efficient CK@PTM internalization into breast cancer cells, potentially attributable to TA-enhanced membrane affinity. Both in vitro and in vivo evaluations demonstrated significant tumor growth suppression of CK@PTM, driven primarily by the synergistic reciprocal potentiation of KAE-augmented Ca²⁺ overload and nanoplatform-induced oxidative stress.​​ ​Furthermore, CK@PTM triggered immunogenic cell death (ICD), as evidenced by damage-associated molecular pattern (DAMP) release, suggesting potential for activating T-cell-mediated antitumor immunity.​​ Collectively, this nanotherapeutic strategy established a proof-of-concept paradigm for bidirectional amplification of calcium-overload and oxidative-stress signaling cascades, presenting a promising approach for solid tumors.