Phagocytosis by brain macrophages in central nervous system diseases: Dual effects, cellular heterogeneity, and targeted therapeutic strategies.

Phagocytosis is a core function of immune cells in the central nervous system (CNS), primarily executed by brain macrophages. This cellular ensemble comprises microglia, border-associated macrophages (BAMs), and peripherally recruited blood-derived macrophages, which collectively regulate brain development, homeostasis maintenance, and disease progression. During the progression of CNS diseases, brain macrophages exhibit dual roles in phagocytic function. Moderate phagocytosis exerts neuroprotective effects, whereas excessive phagocytosis impairs normal neural structures. The underlying regulatory mechanisms are highly complex. Notably, key receptors involved in phagocytosis represent potential therapeutic targets for CNS diseases, and various drugs targeting these receptors to modulate brain macrophage function have demonstrated promising therapeutic potential. In recent years, the emergence of novel drug delivery systems has exerted a positive impact on the clinical translation of such drugs. Nevertheless, systematic summaries of relevant research progress remain lacking. The present review comprehensively elaborates on the physiological functions of brain macrophages, with a primary focus on the regulatory pathways of phagocytosis and their therapeutic value in CNS diseases. It also summarizes strategies for targeted modulation of phagocytic function using natural products, synthetic drugs and biological agents, while exploring the role of advanced delivery systems, including nanogels, liposomes, nanoparticles, nanovesicles, and supramolecular inclusion complexes, in enhancing therapeutic efficacy. Collectively, this review intends to provide a theoretical basis and directional guidance for optimizing therapeutic strategies targeting the phagocytic function of brain macrophages in CNS diseases and advancing the development of novel drug delivery systems.