Manganese-based Virus-mimicking Nanomedicine with Triple Immunomodulatory Functions Inhibits Breast Cancer Brain Metastasis
Time：2025/3/29 13:59:05 Views：8
Brain metastasis is a significant contributor to mortality, impacting one in five cancer patients, with a median survival of merely 4 months. Patients with brain metastasis from triple-negative breast cancer (TNBC) often exhibit resistance to conventional therapeutic modalities due to the impeding influence of the BBB, metastatic tumor heterogeneity, and the immunosuppressive physiopathological environment. Additionally, radiochemotherapy interventions frequently precipitate notable adverse effects and compromised patient outcomes. With the advancement of diagnostic techniques and improvements in the treatment outcomes of primary tumors, the incidence of brain metastasis is continuously increasing. Therefore, there is an urgent demand for the development of efficacious therapeutic approaches with less toxicity to alleviate the treatment challenges posed by brain metastasis.
As research progresses, immunotherapy has emerged as a compelling avenue for treating diverse cancers. However, the reduced immunogenicity of triple-negative breast cancer, combined with the limitations imposed by the central nervous system (CNS) on drug delivery and immune cell infiltration, leads to the exclusion of patients with brain metastasis from clinical trials of immunotherapy. Fortunately, Virus-mimicking nanosystems (VMN) are well-positioned to tackle these challenges. They can be customized to mimic the in vivo viral infection process while minimizing potential genetic risks. Specifically, VMN can retain the immune evasion and tissue tropism traits of viruses, facilitating efficient drug delivery. In addition, it can simulate viral infection processes to activate the cGAS-STING pathway, thereby inducing innate immunity. The VMN has been verified to suppress tumors by activating innate immunity in the orthotopic 4T1 mouse model. Moreover, the activation of innate immunity promotes the onset of adaptive immune response and subsequent T cell infiltration. Furthermore, enhanced infiltration of T cells into brain metastatic loci has been shown to impede metastatic progression. Nevertheless, a strong immunosuppressive microenvironment can undeniably induce therapeutic resistance, markedly hampering the effective application of VMN in treating brain metastatic tumors. Moreover, the heterogeneity of brain metastasis further contributes to limited therapeutic benefit. The majority of drugs exhibit distinct response rates in brain metastasis compared to peripheral tumors. Notably, in breast cancer brain metastasis, microenvironment-dependent epigenetic silencing of PTEN occurs. Specifically, astrocytes release exosomes containing miR-19a, which epigenetically and reversibly suppresses PTEN expression in metastatic cells. This, in turn, triggers STAT3-mediated tumor immune evasion and the development of an immunosuppressive microenvironment. Hence, targeting the degradation of miR-19a can rescue the loss of PTEN and remodel the immunosuppressive microenvironment, effectively inhibiting breast cancer brain metastasis.
Therefore, drawing inspiration from the drug delivery strategy of VMN as well as the therapeutic strategy of immune activation and microenvironmental modulation by cGAS-STING activation and miR 19a-targeted degradation, we engineered a manganese-based virus-mimicking nanomedicine (Vir-HD@HM) with triple immune modulation capabilities. HD, standing for Hollow manganese dioxide nanoparticles (HMnO2) loaded with DNAzyme, can mimic viral genomes to selectively degrade miR-19a and activate cGAS-STING. A hybrid membrane (HM), mimicking viral envelopes, is utilized to prolong the circulation time of Vir-HD@HM and protect DNAzyme from degradation. The D-cskc (hereinafter referred to as cskc) and HA2 peptides mimic viral spikes, enabling BBB penetration and targeting of metastatic loci. The peptides also facilitate rapid escape of endosomes, thereby ensuring DNAzyme activity. Pharmacological analysis in triple-negative breast cancer brain metastasis model mice (BrM-mice) demonstrates that Vir-HD@HM effectively accumulates in metastatic tumors, rescues epigenetic silencing of PTEN, promotes immune cell infiltration, and inhibits STAT3 activation. Ultimately, by activating innate and adaptive immunity as well as ameliorating the immunosuppressive microenvironment, Vir-HD@HM significantly prolongs survival in BrM-mice under non-chemotherapeutic conditions.
Doctoral student Zhao Zhenhao in our group is the first authors of the paper, and Professor Jiang Chen is the corresponding author of the paper. The research was supported by the National Natural Science Foundation of China, the Shanghai Academic Research Leaders Program and other projects.
