Reprogramming macrophage metabolism for cardiovascular therapy: From molecular pathways to precision nanomedicine.

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, largely driven by chronic inflammation and inadequate tissue repair. As central orchestrators of immune homeostasis, macrophages undergo profound metabolic reprogramming that dictates whether inflammation is sustained or resolved. Glycolysis fuels the pro-inflammatory phenotype, whereas oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) support the reparative state. These metabolic transitions are governed by signaling pathways such as mammalian target of rapamycin (mTOR), nuclear factor-κB (NF-κB), peroxisome proliferator-activated receptor γ (PPAR-γ)/liver X receptor (LXR), and nuclear factor erythroid 2-related factor (NRF2), and further stabilized by epigenetic modifications that imprint long-term immunometabolic memory. This review integrates advances in signaling, metabolic, and epigenetic regulation of macrophage reprogramming in CVDs, with a focus on therapeutic strategies that modulate these axes. Particular attention is given to nanomedicine-based delivery systems that enable precise, controlled, and multi-level regulation of macrophage metabolism, overcoming the limitations of conventional therapies. By bridging macrophage immunometabolism with nanoscale intervention, this work outlines a framework for developing macrophage-centered therapeutics aimed at resolving inflammation, stabilizing atherosclerotic lesions, and enhancing cardiac repair, thereby advancing the translation of precision immunometabolic therapies in cardiovascular medicine.