Neural Stem Cell-Derived Extracellular Vesicles for Advanced Neural Repair

Abstract

The limited regenerative capacity of the central nervous system (CNS) severely hinders treatment of neurodegenerative and neuroinflammatory diseases. These conditions, frequently exacerbated by aging, share common hallmarks such as neuroinflammation, demyelination, and neuronal loss. While neural stem cells (NSCs) hold great therapeutic promise due to their paracrine effects, including extracellular vesicle (EV) release, direct transplantation presents significant challenges. This review focuses on NSC-derived EVs as a novel therapeutic strategy, as we explore their multimodal mechanisms in modulating neuroinflammation, promoting neurogenesis, and restoring cellular bioenergetics through the delivery of bioactive molecules and mitochondrial transfer. Recent advances in NSC-EV-based therapies for age-associated neurodegenerative diseases are highlighted, along with key challenges in EV production, preservation, and targeted delivery. Finally, we outline future directions for translating this promising approach into effective clinical treatments.

Keywords: extracellular vesicles (EVs); neural stem cells (NSCs); neurodegeneration; neuroinflammation; regenerative neuroimmunology.

FIGURE 1

Limited endogenous repair potential and main strategies for neural regeneration. (a) Main stem cell‐like populations in the adult brain include neural stem cells (NSCs) or ependymal cells (ECs) located in neurogenic niches such as the subventricular zone (SVZ), subgranular zone (SGZ), amygdala, striatum, cortex, and hypothalamus. Oligodendrocyte precursor cells (OPCs) are distributed throughout the brain and contribute to myelination and neural repair. Perivascular mesenchymal stem cells (MSCs) and pericytes reside in the vascular niche, while brain endothelial cells (BECs) within the blood–brain barrier (BBB) exhibit progenitor‐like properties. (b) Endogenous stem cells possess self‐renewal capacity and multipotency, enabling neurogenesis and gliogenesis. Their function is tightly regulated by the microenvironment, including soluble factors (cytokines, neurotrophins), extracellular vesicles (EVs) carrying signaling molecules and mitochondria, and neuroimmune interactions. However, their repair capacity is inherently limited and declines with aging, inflammation, and metabolic dysfunctions. (c) Advanced therapeutic approaches aim to overcome the limitations of endogenous repair mechanisms. These include: Cell‐based therapies: NSC and MSC transplantation, engineered immune cells (e.g., CAR‐T cells); Cell‐free therapies: EVs, mitochondria‐based biotherapies, neutralizing antibodies (e.g., targeting neurite growth inhibitors), neurotrophic factor delivery, gene therapy, reprogramming strategies (in situ astrocyte/pericyte‐to‐neuron conversion), biomaterial and extracellular matrix‐based approaches (bio scaffolds to support neurogenesis and reduce scarring); Combination strategies: Integrating cell‐based and cell‐free methods for enhanced efficacy. Created by BioRender.

FIGURE 2

Multimodal mechanisms of action of NSC‐EVs. (a) NSC‐EVs enhance neural progenitor proliferation and differentiation through miRNA‐mediated regulation, ERK signaling, and protection against oxidative stress. They also influence oligodendrocyte differentiation via prostaglandin E2 (PGE2) signaling. (b) NSC‐EVs regulate inflammatory responses via various molecular pathways. They transfer IFN‐γ to activate Stat1 signaling in target cells and suppress microglial activation through miRNA‐mediated mechanisms. NSC‐EVs also mitigate inflammatory cell death (pyroptosis) via YBX1 and autophagy‐mediated pathways, reducing pro‐inflammatory cytokine expression. (c) NSC‐EVs protect against oxidative stress, preserve mitochondrial function by transferring intact mitochondria, regulate metabolic homeostasis, and counteract neurotoxic astrocyte activation. Additionally, NSC‐EVs suppress microglial reactivity, modulate inflammatory pathways, and mitigate aging‐associated neurodegenerative processes. Together, these multimodal actions highlight the therapeutic potential of NSC‐derived EVs in CNS repair and regeneration. Created by BioRender.