mRNA-Guided Therapeutic Strategies in Primary and Metastatic Brain Tumors: Platforms, Targets, and Translational Constraints

Messenger RNA (mRNA)-based therapeutics have emerged as a programmable platform with expanding relevance to neuro-oncology, where intracranial disease control remains difficult to achieve. Recent successes in systemic oncology have renewed interest in applying these approaches to primary and metastatic brain tumors. We performed a narrative synthesis of clinical, translational, and mechanistic studies evaluating mRNA-guided therapeutic strategies in glioblastoma (GBM) and brain metastases (BrM). In GBM, clinical experience has been dominated by dendritic cell-mRNA vaccination, which consistently demonstrates feasibility and the ability to induce antigen-specific immune responses, but only limited and inconsistent intracranial efficacy. This discrepancy reflects multiple converging constraints, including profound intratumoral immune suppression, heterogeneous blood-brain and blood-tumor barrier permeability that limits effector access and delivery exposure, and treatment-related immunosuppression, particularly corticosteroid use. Emerging mRNA modalities, including delivery-targeted mRNA systems and mRNA-enabled immune programming strategies such as transient chimeric antigen receptor (CAR) expression or local immunomodulatory payload delivery, offer theoretical advantages in localization, controllability, and safety. However, their translation remains constrained by biodistribution limitations, intratumoral heterogeneity, and uncertainty regarding reliable intracranial exposure across infiltrative tumor compartments. In brain metastases (BrM), systemic mRNA vaccine strategies appear more transferable because they rely primarily on peripheral immune priming rather than direct intracranial payload delivery, aligning with tumor types that already demonstrate responsiveness to immune checkpoint blockade. Nevertheless, intracranial efficacy remains influenced by lesion-level heterogeneity, including variable blood-tumor barrier permeability, differences in immune microenvironment permissiveness across lesions, and discordant intracranial versus extracranial treatment responses. Collectively, these findings indicate that while mRNA platforms are biologically active and mechanistically versatile, durable intracranial benefit depends on matching therapeutic modality to disease-specific delivery, immune, and microenvironmental constraints. mRNA-based therapies are biologically active and feasible in neuro-oncology, but durable intracranial benefits will require disease-specific strategies that explicitly address CNS barriers. Progress will depend on mechanism-driven combinations, steroid-aware trial design, and endpoints that directly assess intracranial immune engagement.