Porphyrin MOF nanosheets loaded with scorpion venom peptide for synergistic chemo-photodynamic cancer therapy.

Conventional cancer treatments often fall short, making multimodal therapies essential. This study introduces a novel hybrid nanoplatform, TCPP-MOF-NS@Smp24, created by immobilizing the scorpion venom peptide Smp24 within porphyrin metal-organic framework nanosheets to combine chemotherapy and photodynamic therapy (PDT). The resulting conjugate showed excellent physicochemical stability, strong photosensitizing properties, and high biocompatibility, with hemolysis indices below 2.5% ensuring safety for systemic use. We evaluated the cytotoxicity of TCPP-MOF-NS@Smp24 against HepG2 (liver), MDA-MB-231 (breast), and HCT-116 (colon) cancer cells, as well as normal human skin fibroblasts (HSF), under dark and light-irradiated conditions. Upon photo-irradiation, the nanoplatform demonstrated highly selective cytotoxicity against all cancer lines, outperforming the standard drug 5-fluorouracil (5-FU) while sparing normal cells. It was most effective against HCT-116 colon cancer cells, achieving an IC50 value of 4.43±0.93μg/mL. Flow cytometry revealed that combining Smp24 with light-activated reactive oxygen species caused mitochondrial dysfunction and membrane portion, triggering apoptosis. Furthermore, the nanoplatform favorably modulated the inflammatory microenvironment; in LPS-stimulated cells, it markedly reduced pro-inflammatory cytokines (TNF-α, IL-6) and IL-13, while upregulating caspase-3 activity to drive programmed cell death in cancer cells. Overall, these findings demonstrate that TCPP-MOF-NS@Smp24 is a potent, multifunctional therapeutic system that effectively combines peptide-driven membrane disruption with PDT to deliver highly selective and efficient cancer therapy.