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

Background: 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.

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

Results: Under the slightly acidic conditions of the TME, the PAA shell (first lock) breaks down first exposing CaO@ZIF8 and CUR inside the cell. Then, ZIF8 (second lock) is degraded in response to acid to deposit Ca, and HO. CUR can promote the release of Ca from the endoplasmic reticulum to the cytoplasm, inhibit the outflow of Ca, and accumulates a large amount of Ca intracellularly together with exogenous Ca (calcium storms). The powerful calcium storm that causes mitochondrial dysfunction. The presence of a large amount of exogenous HO causes further oxidative damage to tumor cell membranes and mitochondria where intracellular ROS production far exceeds clearance. CaO@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.

Discussion: 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 CaO@ZIF8:CUR@PAA as an anticancer platform, paving the way for nanomaterials in immune-triggered cancer therapy.