Calcium overloaded multifunctional composite nanomaterials synergistically treat cancer by ferroptosis pathway

The treatment of pancreatic cancer has long been a global challenge. Strategies based on mitochondrial Ca²⁺ overload-related ferroptosis have garnered significant attention. However, the various limitations of current Ca²⁺ generators make it difficult to maintain an effective concentration of Ca²⁺ overload. In this study, we developed a nanocomposite material, CaO₂@Fe(SS)-MOF@Ce6@PAA (CFMCP), by encapsulating CaO₂ nanoparticles (NPs) and the photosensitizer Chlorin e6 (Ce6) within a metal-organic framework (MOF) and further modifying it with polyacrylic acid (PAA). This nanocomposite effectively depletes glutathione (GSH) in tumor tissues, thereby enhancing the efficacy of photodynamic therapy (PDT) and chemodynamic therapy (CDT). Upon co-incubation of CFMCP NPs with SW1990 pancreatic cancer cells, we observed efficient cellular uptake of the nanomaterials. Under the influence of CFMCP NPs, cellular GSH and glutathione peroxidase 4 (GPX4) levels decreased, exacerbating oxidative stress and lipid peroxidation, increasing Fe²⁺ content, and aggravating mitochondrial damage. Using the mitochondrial Ca²⁺ uptake inhibitor Ruthenium red, we further confirmed that Ca²⁺ overload is a critical mechanism by which CFMCP NPs induce ferroptosis in SW1990 cells. In vivo studies demonstrated that CFMCP NPs exhibit excellent biocompatibility, significantly inhibit tumor growth, and exert direct cytotoxic effects. In summary, the development of this novel composite nanomaterial, which induces ferroptosis through mitochondrial Ca²⁺ overload, provides a valuable reference for synergistic and highly effective tumor therapy.