BACKGROUND: Stroke induces profound neuroinflammation in which macrophages play a complex dual role, contributing to both injury and repair. The traditional M1/M2 classification is increasingly recognized as oversimplified. Advances in single-cell RNA sequencing (scRNA-seq) have revealed a spectrum of dynamic macrophage subpopulations with distinct functional and metabolic states, fundamentally reshaping our understanding of post-stroke immunity. MAIN BODY: This review synthesizes recent insights into macrophage heterogeneity from a single-cell perspective, highlighting novel subsets such as an LCP1⁺ population defined by coupled glycolipid metabolism. We discuss how metabolic reprogramming, including glycolysis, oxidative phosphorylation, cholesterol metabolism, hypoxia‑driven gradients, and mitochondrial dynamics, critically underpins macrophage polarization. Glycolysis fuels pro-inflammatory (M1-like) responses, whereas oxidative phosphorylation and fatty acid oxidation support anti-inflammatory and reparative (M2-like) functions. We further explore innovative nano‑therapeutic strategies, including engineered liposomes, exosomes, and responsive polymeric nanoparticles, that enable spatiotemporally precise modulation of macrophage activity. Based on these advances, we propose an integrative framework that directly links scRNA‑seq‑defined macrophage subsets to their metabolic pathways, druggable targets, and tailored nano‑interventions. We also critically examine clinical translation barriers and prioritize actionable targets (e.g., CCR2, PPARγ, Nrf2) for future stroke therapy. CONCLUSIONS: The convergence of single‑cell genomics, immunometabolism, and nanotechnology offers a transformative path toward precision immunomodulation in stroke. Moving beyond the static M1/M2 dichotomy to target macrophage subpopulations and their metabolic drivers guided by an integrated framework holds significant promise for developing more effective therapies.
Y et al. (Sat,) studied this question.