Membrane-bound supramolecular nanofiber network stimulates transient receptor potential channels for calcium overload cancer therapy

Calcium (Ca2+) overload therapy is an efficient cancer treatment modality that increases aberrant cytoplasmic Ca2+ accumulation and activates mitochondrial apoptotic cascades. Current strategies primarily use exogenous inorganic Ca2+ salts to generate these effects. However, off-target Ca2+ release and the resulting hypercalcemic crisis limit their applications. We here report our serendipitous finding that a self-assembling peptide of NapGFFpYHWYGYTPQNVI (namely N-pGE11), possessing both alkaline phosphatase (ALP)-responsive and epidermal growth factor receptors (EGFR) binding properties, can mobilize the extracellular Ca2+ reservoir for Ca2+ overload therapeutics. N-pGE11 is capable of producing the EGFR-specific nanofibers on HeLa cell membranes in an ALP-responsive manner, which then facilitates extracellular Ca2+ influx and accumulation in the cytoplasm by indirectly stimulating TRP channels. Cytoplasmic Ca2+ overload is transmitted to the mitochondria, thus generating mitochondrial stress and caspase-3-dependent apoptosis. Meanwhile, excess cytoplasmic Ca2+ is also transported into the extracellular space and then results in thorough cell calcification via the secretion of Ca2+-enriched vesicles through exocytotic pathways. Consequently, N-pGE11 effectively inhibits tumor growth with good biocompatibility, whereas its therapeutic efficacy is enhanced significantly by feeding mice a highcalcium diet.