Acid-Unlocked Two-Layer Ca-Loaded Nanoplatform to Interfere With Mitochondria for Synergistic Tumor Therapy

The development of selective formulations able to target and kill tumor cells without the application of external energy has shown great promise for anti-tumor therapy.

Here, we report a "nanobomb" that explosively increases Ca content within cells. It can selectively release Ca²⁺ and generate H₂O₂ in the tumor microenvironment (TME) by acid-triggered degradation of the two-layer protective shell (ie, unlocking the "double-lock"). This material, termed CaO₂@ZIF8:CUR@PAA, comprises a CaO₂ core coated with the ZIF-8 framework, which was then loaded with curcumin (CUR) and coated again with polyacrylic acid (PAA).

Under the slightly acidic conditions of the TME, the PAA shell (first lock) breaks down first exposing CaO₂@ZIF8 and CUR inside the cell. Then, ZIF8 (second lock) is degraded in response to acid to deposit Ca²⁺, and H₂O₂. CUR can promote the release of Ca²⁺ from the endoplasmic reticulum to the cytoplasm, inhibit the outflow of Ca²⁺, and accumulates a large amount of Ca²⁺ intracellularly together with exogenous Ca²⁺ (calcium storms). The powerful calcium storm that causes mitochondrial dysfunction. The presence of a large amount of exogenous H₂O₂ causes further oxidative damage to tumor cell membranes and mitochondria where intracellular ROS production far exceeds clearance. CaO₂@ZIF8:CUR@PAA NPs can induce cell S cycle arrest and apoptosis to inhibit tumor multiplication and growth. Oxidative damage-triggered immunogenic cell death (ICD) in turn leads to the polarization of macrophages to the M1 phenotype, inducing immunogenic cell death and inhibiting tumor cell proliferation and metastasis.

The acid two-step unlocking nanoplatform is a therapeutic modality that combines calcium storm and oxidative damage. The mode triggers apoptosis leading to ICD of tumor cells. The material induces cycle blockade during treatment to inhibit cell proliferation. Robust in vitro and in vivo data demonstrate the efficacy of this approach and CaO₂@ZIF8:CUR@PAA as an anticancer platform, paving the way for nanomaterials in immune-triggered cancer therapy.