Polymersome-enabled brain codelivery of STAT3 siRNA and CpG oligonucleotide boosts chemo-immunotherapy of malignant glioma.

Malignant glioma represents one of the most aggressive primary tumors of the central nervous system. The immunotherapy of glioma is restrained by low immunogenicity, an immunosuppressive environment, and challenges in delivering therapeutics and immune-modulating agents. Here, we demonstrate that the systemic brain codelivery of STAT3 siRNA and CpG oligonucleotide using ApoE peptide-functionalized nano-polymersomes (tNano-S&C) significantly boosts the efficacy of chemo-immunotherapy for malignant glioma when combined with temozolomide (TMZ). The administration of STAT3 siRNA via tNano-S&C effectively knocked down STAT3 expression in glioma cells, resulting in increased sensitivity to TMZ treatment and enhancing immunogenic cell death. Furthermore, tNano-S&C was efficiently taken up by dendritic cells (DCs), inducing DC maturation and proinflammatory cytokine secretion. Interestingly, intravenous injections of tNano-S&C in orthotopic murine glioma LCPN models revealed elevated accumulation at the tumor site, in cervical lymph nodes (CLNs) and the spleen, and within antigen-presenting cells (APCs). This delivery system effectively enhanced the outcomes of chemo-immunotherapy with TMZ, leading to a marked extension of median survival time and complete regression in 25% mice. tNano-S&C treatment reduced M2 phenotype glioma associated macrophages and regulatory T cells, while increasing the recruitment of cytotoxic T lymphocytes. These findings suggest that this polymersome-enabled brain codelivery of STAT3 siRNA and immunoadjuvants provides an appealing strategy to effectively reshape the tumor immune microenvironment and boost the efficacy of chemo-immunotherapy of malignant glioma.