Hyaluronic acid-mediated targeted nano-modulators for activation of pyroptosis for cancer therapy through multichannel regulation of Ca2+ overload.

Calcium-based nanomaterials-mediated Ca2+ overload-induced pyroptosis and its application in tumor therapy have received considerable attention. However, the calcium buffering capacity of tumor cells can maintain mitochondrial calcium homeostasis, so it is important to effectively disrupt this homeostasis to activate pyroptosis. Here, a nano-modulator CUR@CaCO3-PArg@HA (CCAH) was developed to regulate calcium overload in multiple channels and activate pyroptosis. Hyaluronic acid (HA)-coated nano-modulators achieve tumor targeting, and under the weakly acidic conditions of the tumor microenvironment (TME), CaCO3 nanoparticles rapidly release curcumin (CUR), inhibit the outflow of intracellular Ca2+, and release exogenous Ca2+. Meanwhile, poly-L-arginine (PArg) reacts with reactive oxygen species (ROS) generated by mitochondrial imbalance, releasing nitric oxide (NO) and stimulating the endoplasmic reticulum to release endogenous Ca2+. The combined action of endogenous and exogenous Ca2+ effectively activates caspase-1, which cleaves gasdermin-D (GSDMD) to produce the active N-terminus (GSDMD-N), effectively activating pyroptosis. Notably, the generated ROS and NO can also generate more oxidizing ONOO-, further exacerbating the imbalance in mitochondrial homeostasis. This work demonstrates that simultaneous modulation of exogenous and endogenous Ca2+ can disrupt mitochondrial Ca2+ homeostasis and effectively activate pyroptosis to treat tumors, which is expected to promote the progression of cancer treatment in the future.