Manganese-based virus-mimicking nanomedicine with triple immunomodulatory functions inhibits breast cancer brain metastasis

Hindered by the challenges of blood-brain barrier (BBB) hindrance, tumor heterogeneity and immunosuppressive microenvironment, patients with breast cancer brain metastasis have yet to benefit from current clinical treatments, experiencing instead a decline in quality of life due to radiochemotherapy. While virus-mimicking nanosystems (VMN) mimicking viral infection processes show promise in treating peripheral tumors, the inability to modulate the immunosuppressive microenvironment limits the efficacy against brain metastasis. Accordingly, a VMN-based triple immunomodulatory strategy is initially proposed, aiming to activate innate and adaptive immune responses and reverse the immunosuppressive microenvironment. Here, manganese-based virus-mimicking nanomedicine (Vir-HD@HM) with intratumoral drug enrichment is engineered. Vir-HD@HM can induce the immune response through the activation of cGAS-STING by mimicking the in vivo infection process of herpesviruses. Meanwhile, DNAzyme mimicking the genome can rescue the epigenetic silencing of PTEN with the assistance of Mn²⁺, thus ameliorating the immunosuppressive metastatic microenvironment and achieving synergistic sensitizing therapeutic efficacy. In vivo experiments substantiate the efficacy of Vir-HD@HM in recruiting NK cells and CD8⁺ T cells to metastatic foci, inhibiting Treg cells infiltration, and prolonging murine survival without adjunctive radiochemotherapy. This study demonstrates that Vir-HD@HM with triple immunomodulation offers an encouraging therapeutic option for patients with brain metastasis.