Mechanisms underlying neuroimmune networks as central regulators in combating neurodegenerative diseases

Neuroimmune dysregulation is increasingly recognized as a key driver in the pathogenesis of neurodegenerative diseases. In addition to local glial responses within the central nervous system, neuroimmune dysregulation also involves peripheral immune activities and inter-organ communication networks. As previous studies have primarily concentrated on individual peripheral organs or specific immune cell types, the broader systemic immune network remains insufficiently investigated. To delay the onset and progression of neurodegenerative diseases, this review evaluates the latest therapeutic strategies and proposes feasible directions for the rational design of optimal immunomodulatory approaches. By focusing on central nervous system-intrinsic regulatory mechanisms, we delineate how microglia adopt context-dependent phenotypes and further elucidate the dynamic regulatory roles of astrocytes in maintaining blood-brain barrier integrity and synaptic homeostasis. Based on these insights, we propose a feasible direction for achieving a functional balance between neuroprotective phagocytosis and the regulation of chronic neuroinflammation. Furthermore, recent evidence indicates that peripheral immune populations, together with the central nervous system, also play a critical role in the therapeutic regulation of neurodegenerative diseases. As key components of peripheral immune populations, specific T-cell subsets can exert neuroprotective or neurotoxic effects, while B cells and macrophages also make notable contributions through antibody-independent mechanisms and metabolic reprogramming. This review outlines systemic pathways that connect peripheral organs to the brain, demonstrating how gut-derived metabolites, pulmonary immune responses, and renal-hepatic clearance collectively shape the immune regulation of the central nervous system. To achieve cell-specific modulation through neuroimmune pathways, this review further investigates glia-targeted therapeutic strategies, particularly in the areas of small molecules, biologics, and nanocarrier-based platforms. Meanwhile, this review also summarizes the current progress and limitations in neuroimmune-targeted drug development and offers valuable guidance for advancing future drug design. In summary, by integrating the analyses of single cells and multi-omics and utilizing organoid-based modeling, this review highlights the vital transition from broad immunosuppression to precision immunoregulation and proposes a novel regulatory framework spanning from the central to peripheral systems. It further offers targeted and feasible recommendations to advance neuroimmunology from theoretical exploration toward practical therapeutics. However, the implementation of these strategies still faces challenges from the temporal dynamics of immune activation, which could be potentially resolved by the enhancement of human glial cell-based biomimetic models and the improvement of stage-specific biomarkers.