Boosting Glioblastoma Therapy with Targeted Pyroptosis Induction

Glioblastoma (GBM) is a highly aggressive cancer that currently lacks effective treatments. Pyroptosis has emerged as a promising therapeutic approach for cancer, but there is still a need for new pyroptosis boosters to target cancer cells. In this study, it is reported that Aloe‐emodin (AE), a natural compound derived from plants, can inhibit GBM cells by inducing pyroptosis, making it a potential booster for pyroptosis‐mediated GBM therapy. However, administering AE is challenging due to the blood‐brain barrier (BBB) and its non‐selectivity. To overcome this obstacle, AE@ZIF‐8 NPs are developed, a biomineralized nanocarrier that releases AE in response to the tumor's acidic microenvironment (TAM). Further modification of the nanocarrier with transferrin (Tf) and polyethylene glycol‐poly (lactic‐co‐glycolic acid) (PEG‐PLGA) improves its penetration through the BBB and tumor targeting, respectively. The results show that AE‐NPs (Tf‐PEG‐PLGA modified AE@ZIF‐8 NPs) significantly increase the intracranial distribution and tumor tissue accumulation, enhancing GBM pyroptosis. Additionally, AE‐NPs activate antitumor immunity and reduce AE‐related toxicity. Overall, this study provides a new approach for GBM therapy and offers a nanocarrier that is capable of penetrating the BBB, targeting tumors, and attenuating toxicity. By wrapping transferrin (Tf) modifies polyethylene glycol‐poly (lactic‐co‐glycolic acid) polymer on the surface of aloe‐emodin (AE) loaded ZIF‐8, a blood–brain barrier penetrating, glioblastoma (GBM) targeting and pyroptosis boosting nanoformulation is developed. The nanoformulation significantly increases the tissue distribution of intracranial and GBM, and enhances the antitumor activity of AE via CASP3/GSDME pathway induced cell pyroptosis and antitumor immune activation.