Engineered immune-driven theranostics for clinical cardiology

Figures

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  Fig. 1. Schematic overview of engineered immune-driven nanotheranostics for clinical cardiology. Immune cells, including macrophages, neutrophils, regulatory T cells (Tregs), mast cells, dendritic cells (DCs), natural killer (NK) cells, and B cells play critical roles in cardiovascular diseases (CVDs). Nanomaterials modulate these immune responses to achieve both nanodiagnostic and nanotherapeutic outcomes. Nanodiagnostic platforms enable targeted imaging of immune cells and inflammatory microenvironments within cardiovascular lesions, supporting precise disease monitoring. Nanotherapeutics regulate multiple aspects of immune activity, including chemotaxis, proliferation, death modes, and functional responses such as excessive inflammation, phagocytosis, macrophage polarization, and neutrophil extracellular trap (NETs) formation. These integrated strategies offer potential applications in major cardiovascular pathologies, including atherosclerosis, myocardial infarction, ischemic stroke, abdominal aortic aneurysm, and myocarditis, thereby establishing a foundation for precision cardiovascular medicine

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  Fig. 2. Role of macrophages in CVDs. Monocytes adhere to and transmigrate across activated ECs via selectin- and integrin-mediated interactions. Under inflammatory stimuli, they differentiate into pro-inflammatory M1 macrophages, which drive vascular inflammation, FC formation, impaired efferocytosis, ECM degradation, and plaque destabilization through ROS and cytokine release. As inflammation resolves, macrophages polarize toward the M2 phenotype, exerting anti-inflammatory, lipid-regulatory, and tissue-repairing functions by enhancing cholesterol efflux, stimulating fibroblast proliferation, and promoting ECM reconstruction. PSGL-1 P-selectin glycoprotein ligand-1, CCR C-C motif chemokine receptor, CCL C-C motif chemokine ligand, LFA-1 lymphocyte function-associated antigen-1, VLA-4 very late antigen-4, VCAM-1 vascular cell adhesion molecule-1, ICAM-1 intercellular adhesion molecule-1, M-CSF macrophage colony-stimulating factor, DC dendritic cell, M1 macrophage classically activated macrophage phenotype, M2 macrophage alternatively activated macrophage phenotype, iNOS inducible nitric oxide synthase, IL Interleukin, TNF-α tumor necrosis factor-α, NLRP3 NOD-like receptor family pyrin…

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  Fig. 3. Role of neutrophils in CVDs. Neutrophils adhere to and transmigrate across activated endothelial cells via selectin- and integrin-mediated interactions. Activated neutrophils release ROS, proteases, and granule proteins, promoting endothelial dysfunction, FC formation, ECM degradation, and inflammation. Neutrophil extracellular traps (NETs) further amplify immune activation through inflammasomes and pDC-derived IFN-α, contributing to thrombus formation and Th17 responses. Conversely, neutrophil-derived mediators such as cathelicidin, NGAL, and annexin A1 promote vascular repair via EPC activation, M2 polarization, and angiogenesis. PSGL-1 P-selectin glycoprotein ligand-1, CXCL C-X-C motif chemokine ligand, CXCR C-X-C motif chemokine receptor, LFA-1 lymphocyte function-associated antigen-1, Mac-1 macrophage-1 antigen, ICAM intercellular adhesion molecule, LDL low-density lipoprotein, MPO myeloperoxidase, NETs neutrophil extracellular traps, NE neutrophil elastase, pDCs plasmacytoid dendritic cells, IFN-α interferon-α, NLRP3 NOD-like receptor family pyrin domain containing 3, AIM2 absent in melanoma 2, IL interleukin, VSMCs vascular smooth muscle cells, CCL C-C motif chemokine…

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  Fig. 4. Regulatory roles of Tregs in cardiovascular diseases. Tregs exert immunosuppressive effects in CVDs through the secretion of anti-inflammatory cytokines (e.g., TGF-β, IL-35, IL-10) and the expression of inhibitory molecules such as CTLA-4. By suppressing APCs and effector T cells, Tregs attenuate local immune activation. They also modulate macrophage polarization by promoting M2 phenotypes while inhibiting M1-driven inflammation, thereby reducing pro-inflammatory cytokines and ECM degradation. In addition, Tregs limit B-cell-mediated antibody production, inhibit SMC apoptosis via NF-κB and ERK1/2 pathways, and collectively contribute to vascular protection and tissue homeostasis. Tregs regulatory T cells, CVDs cardiovascular diseases, TGF-β transforming growth factor-β, IL interleukin, CTLA-4 cytotoxic T-lymphocyte-associated protein 4, APCs antigen-presenting cells, M2 macrophage alternatively activated macrophage phenotype, M1 macrophage classically activated macrophage phenotype, ECM extracellular matrix, SMC smooth muscle cell, NF-κB, nuclear factor kappa-B, ERK1/2 extracellular signal-regulated kinase 1/2, ICAM-1 intercellular cell adhesion molecule-1, MMP matrix…

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  Fig. 5. Comprehensive modulation of immune cell-mediated inflammatory responses by nanomaterials. a Nanomaterials can modulate chemokines and their receptors to effectively suppress the migration and infiltration of immunocytes, thereby attenuating inflammatory responses. Current strategies encompass gene silencing of adhesion molecules and chemokines, inhibition of associated signaling pathways, direct neutralization of chemokines, as well as the use of “cell hitchhiking” approaches to achieve precise targeted delivery. b Nanomaterials regulate immune cell proliferation, suppressing pro-inflammatory responses while promoting protective immune functions to modulate the progression of CVDs. c Nanomaterials regulate immune cell functions through multiple mechanisms, including inhibition of inflammatory signaling pathways, ROS scavenging, modulation of phagocytosis, promotion of M2 macrophage polarization, and suppression of NETs formation. These strategies collectively attenuate inflammation, facilitate tissue repair, and preserve cardiovascular function within interconnected immune regulatory networks. d Nanomaterials modulate immune cell death modes to alleviate inflammation and protect…