Bacteria-mediated metformin-loaded peptide hydrogel reprograms the tumor immune microenvironment in glioblastoma

The tumor immune microenvironment (TIME) is one of the significant hallmarks of cancer and has the important role of largely determining the malignancy level of tumors. As an approach to break through this bottleneck of tumor treatment methods, the TIME can be reprogrammed by certain nanomaterials. Here, we coated C-novyi-spores with melittin-RADA₃₂ nanofiber hybrid peptide and loaded the immunomodulator metformin to obtain MRM-coated spores as a powerful antitumor nanodrug against glioblastoma (GBM), which is based on the activation of the TIME. MRM-coated spores exhibit extended-release profiles and an enhanced killing effect on GBM both in vitro and in vivo. Furthermore, MRM-coated spores can educate the innate and adaptive immune system by inducing sustainable CD8⁺ T cell responses, promoting M1 macrophage polarization, and regulating the expression of HIF1-α, PDL1, and CXCL9 in TIME. In intracranial applications, MRM-coated spores showed excellent biosafety and a strong therapeutic effect. In summary, peptide hydrogels provide a promising strategy in which advantages of different treatment methods can be incorporated to synthesize potent antitumor drugs with mild side effects from bacteria-mediated nanomaterials.