From Target Discovery to Spatial Delivery: A Translational Roadmap for Gene-Targeted Therapies in Glioma

Diffuse gliomas are increasingly defined by molecular alterations, yet the clinical translation of gene-targeted therapies remains constrained by a persistent mismatch between target biology and spatial pharmacology. In this review, we connect target discovery to clinical development by integrating spatial and longitudinal tumor biology with payload selection, delivery engineering, biomarker design, manufacturing, and mechanism-driven trials. Recent clinical practices in locoregional CAR-T cells, oncolytic and gene-delivery viruses, tumor-homing myeloid cell gene therapy, mutation- and neoantigen-directed vaccination, RNA nanomedicines, and emerging genome-editing strategies suggest that vehicle and route of administration dramatically change drug exposure, therapeutic index, immune activity, and resistance. We therefore propose the concept of "delivery-adjusted targetability," in which a candidate target is judged not only by biological dependency but also by clonality, longitudinal stability, normal-brain expression, anatomical distribution, modality compatibility, and achievable target engagement. We further argue that the clinically actionable unit in diffuse glioma is often a target-anatomical compartment pair rather than a molecular target considered in isolation. Moreover, we advocate target-payload-vehicle-route-biomarker co-design and a stage-gated evidence package. This framework provides a potential way to compare otherwise dissimilar platforms, distinguish target failure from delivery failure, and reject biologically attractive but spatially implausible programs earlier. Treating molecular dependency and spatial access as a single design problem can make precision neuro-oncology more experimentally falsifiable and clinically actionable.