Replace, Reprogram, and Relay: A Framework for Glial Cell and Extracellular Vesicle Therapies in CNS Repair

Glial cells shape inflammatory resolution, metabolic support, debris clearance, axonal preservation, and myelin repair after CNS injury and neurodegeneration. These functions have motivated two related but non-equivalent therapeutic strategies, either the transplantation and replacement of living glia or the delivery of glia-derived extracellular vesicles (EVs). A viable cell graft can persist, migrate, phagocytose, integrate with host tissue, and adapt its transcriptional and secretory programs after administration. EVs cannot reproduce these autonomous cellular functions, but they can transfer proteins, lipids, metabolites, and nucleic acids as finite, engineerable packages that may be repeated. Microglia provide the principal comparison because the same lineage can be transplanted, replaced, genetically engineered, or used to generate therapeutic EVs. Strategies targeting the microglial compartment include CNS-wide niche repopulation and pathology-responsive engineering, with early human evidence from hematopoietic transplantation in a small uncontrolled cohort with CSF1R-associated microgliopathy, whereas glial EV therapeutics remain predominantly preclinical. Producer-cell state is also critical because microglial EVs can support repair or propagate inflammatory and proteopathic signals. We compare glial cell and EV strategies across CNS trauma and neurodegeneration in terms of biological capability, evidence level, biodistribution, potency, manufacturing, and safety. The proposed framework separates two questions: (1) whether pathology requires replacement of a missing or intrinsically defective cellular population or function (Replace) versus changing the functional state of surviving recipient cells without replacing the population (Reprogram), and, when applicable, (2) what spatial and temporal delivery (Relay) is required, including whether exposure must be local and persistent or distributed and repeatable. Because matched cell-versus-EV studies are rare and the evidence base is asymmetric, this framework is a mechanistic guide for hypothesis generation rather than a ranking of platform efficacy in specific neurological injury or disease paradigms.