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

Fig. 1. Macrophage metabolic reprogramming as a therapeutic axis in cardiovascular diseases (CVDs). This schematic summarizes macrophage metabolic reprogramming as a therapeutic strategy across major CVD contexts, including atherosclerosis, myocardial infarction, heart failure, and myocarditis. Macrophage functional states are regulated by multilevel mechanisms, including signaling pathways, metabolic circuits, and epigenetic programs. Representative signaling nodes include mammalian target of rapamycin (mTOR), nuclear factor-κB (NF-κB), peroxisome proliferator-activated receptor γ (PPAR-γ), and nuclear factor erythroid 2-related factor 2 (NRF2). Core metabolic circuits include glycolysis, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and the tricarboxylic acid (TCA) cycle. Therapeutic modalities, including small-molecule drugs, gene-based therapies, active proteins, and nanomedicine platforms, can be used to modulate these mechanisms. Nanoplatforms such as lipid-based, polymeric, inorganic, and biomimetic nanoparticles may improve lesion-targeted delivery, controlled release, and combination therapy for macrophage-centered cardiovascular intervention (created with…

Fig. 2. Signaling pathways driving macrophage metabolic reprogramming in cardiovascular diseases (CVDs). This schematic illustrates the divergent molecular pathways and metabolic shifts that dictate the functional transition between pro-inflammatory (left) and reparative (right) macrophage phenotypes. Left: Pro-inflammatory polarization is primarily driven by Toll-like receptor (TLR) signaling through the myeloid differentiation primary response 88-TNF receptor associated factor 6 (MyD88-TRAF6) axis and the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) axis which leads to mammalian target of rapamycin complex 1 (mTORC1) activation and transcription factor EB (TFEB) modulation. These cascades culminate in the activation of nuclear factor-κB (NF-κB) and the stabilization of hypoxia-inducible factor-1α (HIF-1α), which collectively promote a metabolic shift toward aerobic glycolysis and the expression of pro-inflammatory markers such as nitric oxide synthase (iNOS). Right: The reparative program is orchestrated by anti-inflammatory signaling through the signal transducer and activator of transcription 6 (STAT6) axis, as well as the activation of AMP-activated protein kinase (AMPK)…

Fig. 3. Core metabolic programs governing macrophage polarization. This schematic illustrates the metabolic reprogramming that orchestrates the functional divergence between pro-inflammatory (left) and reparative (right) macrophages. Left panel (pro-inflammatory macrophage reprogramming): Upon activation, macrophages undergo a profound metabolic shift toward aerobic glycolysis (the Warburg effect), characterized by increased glucose uptake via glucose transporter 1 (GLUT1) and the conversion of pyruvate to lactate. The tricarboxylic acid (TCA) cycle is functionally fragmented at two distinct checkpoints: isocitrate dehydrogenase (IDH) and succinate dehydrogenase (SDH). This “broken” cycle leads to the accumulation of succinate and citrate, citrate can be used for fatty acid synthesis. Accumulated succinate acts as a signaling metabolite that stabilizes hypoxia-inducible factor-1α (HIF-1α), subsequently driving the transcription of the pro-inflammatory cytokine interleukin-1β (IL-1β). Furthermore, an increased pentose phosphate pathway (PPP) and NADPH oxidase activity promote the generation of reactive oxygen species (ROS) and nitric oxide (NO), reinforcing inflammatory functions. These…

Fig. 4. Epigenetic and metabolic memory as stabilizers of macrophage reprogramming. This schematic delineates the temporal process of innate immune memory and the underlying molecular mechanisms that stabilize macrophage phenotypes. (a) Process of trained immunity: The timeline illustrates the functional “memory” of innate immune cells. Primary stimulation by exogenous triggers (e.g., β-glucan, lipopolysaccharide (LPS), or Bacillus Calmette-Guérin (BCG)) induces an initial activation phase characterized by histone H3 lysine 4 trimethylation (H3K4me3) enrichment and active gene transcription. During the subsequent resting phase, macrophages revert to a quiescent state but retain specific epigenetic marks (e.g., H3K4me1). Upon restimulation by various pathogens, these “trained” macrophages exhibit a rapid and heightened reactivation, characterized by increased H3K4me3 levels and increased production of inflammatory mediators, demonstrating how histone modifications encode an enhanced secondary response. (b) Molecular basis of immune training: This panel highlights the interface between metabolic pathways and epigenetic enzymes in the nucleus. Pro-inflammatory reprogramming (left) is fueled…

Fig. 5. Small-molecule modulators of signaling pathways for macrophage metabolic reprogramming. This schematic illustrates how various synthetic and natural compounds target metabolic and antioxidant hubs to promote the transition from pro-inflammatory to reparative macrophage phenotypes. (a) nuclear factor erythroid 2-related factor (NRF2) signaling pathway and antioxidant reprogramming: This panel depicts the therapeutic activation of the AMP-activated protein kinase-NRF2 (AMPK-NRF2) axis. Pharmacological agents such as metformin, dimethyl fumarate, and curcuminoids stimulate AMPK, which in turn facilitates the nuclear translocation of NRF2. Once in the nucleus, NRF2 orchestrates an antioxidant program that reduces reactive oxygen species (ROS) and enhances oxidative phosphorylation (OXPHOS). This metabolic shift reprograms macrophages toward a reparative state, effectively suppressing systemic inflammatory responses. (b) Peroxisome proliferator-activated receptor γ (PPAR-γ) signaling pathway and lipid homeostasis: This panel highlights the modulation of the PPAR-γ/liver X receptor (PPAR-γ/LXR) pathways to facilitate lipid efflux and limit atherosclerosis. Natural products (e.g.,…

Fig. 6. Small-molecule interventions in macrophage metabolic reprogramming. (a) Targeting signaling pathways and mitochondrial dynamics: This panel illustrates the use of small-molecule inhibitors and activators to disrupt pro-inflammatory signaling hubs. Mitochondrial division inhibitor-1 (Mdivi-1) and an SIRT1 activator (SRT1720) modulate mitochondrial dynamics and oxidative stress. Saracatinib interferes with kinase and chemokine signaling, while 2-deoxy-D-glucose (2-DG) and AZ67 directly inhibit the mammalian target of rapamycin (mTOR) and nuclear factor-κB (NF-κB) axes. By restraining glycolysis and pro-inflammatory signaling, these compounds redirect macrophages from a chronic inflammatory state toward a reparative phenotype. (b) Targeting metabolic enzymes and lipid flux: This panel highlights agents that directly modulate enzymatic activity to restore metabolic homeostasis. The pharmacologic inhibitor 4methylthio-2-oxobutyric acid (MTOB), tanshinone IIA, and RvT4 facilitate the switch toward oxidative phosphorylation (OXPHOS)-dependent anti-inflammatory programs. TREM2 agonists enhance fatty acid oxidation (FAO) and promote cholesterol efflux, thereby increasing mitochondrial…

Fig. 7. Nanomedicine-based platforms for macrophage reprogramming. This schematic categorizes the four primary classes of nanocarriers used to deliver therapeutic agents, highlighting their structural diversity and functional trade-offs in the context of macrophage reprogramming. Polymeric carriers, including polymersomes, dendrimers, micelles, nanospheres, and nanofibers, are characterized by high lesion accumulation and low immunogenicity, though they face challenges regarding complex synthesis and limited loading capacity. Inorganic nanoparticles, such as silica, iron oxide, gold nanoparticles, quantum dots, and a mannan (Man)-functionalized nano-metal-organic framework (MOF), offer superior catalytic activity and structural stability under hemodynamic stress, yet are hindered by potential bioaccumulative toxicity and poor degradability. Lipid-based systems, encompassing liposomes, lipid nanoparticles, emulsions, and extracellular vesicles, provide a gold standard for efficient mRNA/siRNA delivery and high bioavailability, but are often limited by poor storage stability and non-specific distribution. Finally, biomimetic carriers, such as microvesicles and protein-based nanostructures,…

Fig. 8. Nanomedicine-based strategies to reprogram macrophage metabolism in cardiovascular diseases. (a) Electrospun PCL/DMI nanofibers constructed from poly-ε-caprolactone and dimethyl itaconate (DMI) downregulate pro-inflammatory genes, reprogram macrophages to reparative types, and protect against myocardial infarction; (b) Proposed mechanism illustrates suppression of inflammation-associated pathways and promotion of reparative macrophage polarization; (c) Quantitative infarct area ratio in nanofiber patches is reduced and the degree of reduction is improved significantly along with the increase of DMI amount in the PCL nanofibers; (d-e) Masson's Trichrome staining of the infarct area confirms myocardial protection in mice treated with PCL/DMI nanofibers; Panels (a-e) reproduced with permission [212]. Copyright 2021, Small; (f) Schematic of DSS/PB@BSP nanoparticles, in which dextran sulfate sodium targets macrophage scavenger receptors and prussian blue nanoparticles provide antioxidative capacity while carrying the anti-inflammatory drug betamethasone sodium phosphate (BSP); (g) Proposed mechanism of DSS/PB@BSP, showing reactive oxygen species scavenging and nuclear factor-κB…

Fig. 9. Nanomedicine-based approaches for metabolic and phenotypic remodeling. (a) Schematic illustration of the construction of CsA@PPTK: a Tregs biomimetic nanoparticle (CsA@PPTK) is prepared by using CsA@ PTK as core and platelet membrane as shell; (b) Proposed mechanism for CsA@PPTK to perform a range of functions such as inflammation inhibition, reactive oxygen species (ROS) elimination and apoptosis inhibition; (c-d) IL-1β and TGF-β concentration in heart tissue of myocardial infarction/reperfusion injury (MI/RI) mice at 4 days after reperfusion are decreased; (e-f) Statistical results of the scar area and the left ventricle area show that CsA@PPTK reduced myocardial fibrosis; (g) Statistical results of fluorescence intensity of CD86/CD206 confirm the ratio of reparative type to pro-inflammatory type macrophages was increased; Panels (a-g) reproduced under terms of the CC-BY license [215]. Copyright 2022, Fangyuan Li, published by J Nanobiotechnology; (h) Schematic illustration of the construction of FNLM-miR: the nanovesicle is coated on MSNs-miR by co-extrusion to form FLM-miR; (i) Proposed mechanism for FNLM-miR to induce direct reprogramming; (j-l) Masson's Trichrome-stained…

Fig. 10. Nanomedicine-based approaches to macrophage reprogramming by targeting inflammatory signaling pathways. (a) Schematic illustration of HA@LSS-EVs construction: sulfhydryl groups of laminar shear stress-induced EVs (LSS-EVs) were conjugated with HA-PEG-MAL to obtain HA@LSS-EVs; (b) Proposed mechanism showing HA@LSS-EVs carrying miR-34c-5p reprogram the pro-inflammatory macrophages into reparative types via the TGF-β-Smad3 pathway; (c-d) Quantitative analysis of CD86 and CD206 confirming the macrophage phenotype shift induced by HA@LSS-EVs; (e-f) Quantification of plaque area and aortic lesions showing significant lesion reduction in HA@LSS-EV-treated groups; (g) ORO-stained aortic trees demonstrating decreased lesion burden following HA@LSS-EV therapy; Panels (a-g) reproduced with permission [219]. Copyright 2025, Biomaterials; (h) Schematic illustration of PLM-miRs preparation: platelet-like fusogenic liposomes (PLPs) are used to encapsulate miR-21-loaded mesoporous silica nanospheres, forming PLM-miRs; (i) Cellular internalization of PLM-miRs and proposed mechanism for macrophage reprogramming from pro-inflammatory macrophages into reparative types; (j) Statistical analysis of…

Fig. 11. Nanomedicine-based approaches to macrophage reprogramming by targeting inflammatory nuclear factor-κB (NF-κB) pathways. (a) Synthetic route of quercetin-loaded mannan (Man)-functionalized nano-metal-organic framework (Que@MOF/Man) nanoparticles: quercetin (Que) is loaded into porous mannan (Man)-functionalized nano-MOFs, followed by mannan coating via electrostatic adsorption; (b) Proposed mechanism of Que@MOF/Man: alleviation of oxidative stress in macrophages, repolarization from pro-inflammatory macrophages to reparative phenotypes, induction of anti-inflammatory cytokines (IL-10, TGF-β1), and cardioprotective effects; (c-e) Flow cytometry analysis showing decreased CD86+ and increased CD206+ macrophages, together with ELISA quantification of inflammatory cytokines (IL-1β, TNF-α), confirming effective macrophage subtype redistribution after Que@MOF/Man treatment; (f-h) Masson's trichrome staining and quantitative analysis of fibrosis and left ventricular wall thickness demonstrating attenuated fibrosis and improved myocardial preservation in Que@MOF/Man group; Panels (a-h) reproduced under CC-BY license [14]. Copyright 2024, Advanced Science; (i) Schematic illustration of…