Research progress on the advantages, mechanisms and design strategies of nanomaterials for immunomodulatory angiogenesis

Abstract

Owing to the difficulty in achieving effective and timely vascularization, repairing the structure and function of damaged tissues and organs remains a major challenge in clinical practice. The immune microenvironment is a key factor affecting angiogenesis; however, traditional strategies have failed to take full advantage of this property. Recent advances in nanomaterial design have shifted from "immune avoidance" to "immune interaction", representing a breakthrough in promoting angiogenesis. An increasing number of studies have reported that nanomaterials(NMs) can induce and regulate immune cells or immune metabolic reprogramming to promote angiogenesis, but few studies have investigated the specific mechanism by which NMs affect immune cells and how they are involved in different stages of angiogenesis. This article reviews the advantages of NMs and focuses on the specific mechanisms by which NMs regulate immune cells, including immune extracellular regulation (changes in the physical and chemical environment), the regulation of membrane receptors and membrane potential, and regulation within immune cells, such as the metabolic activity of immune cells. According to the application scenarios of tissue regeneration (bone, skin, nerve and cardiovascular tissue), the influencing factors and design smart nanomaterials through immune regulation are summarized, and the current challenges and development directions of NMs in clinical applications are proposed, particularly in precision medicine and clinical transformation. This review provides a theoretical basis for an in-depth understanding of NMs and immunomodulatory vascularization for tissue regeneration to optimize the design strategy, rational development and clinical application of NMs in the field of immunovascularization.

Keywords: Angiogenesis; Immune metabolic reprogramming; Nanomaterials; Precision immunomodulation; Smart nanomaterials; Tissue regeneration.

Graphical abstract

Fig. 1

Surface-functionalized NMs target immune cells to promote vascularized tissue regeneration. A. Schematic illustrating the study design of dECM-decorated 3D expanded nanofiber scaffolds that regulate immune cells to promote vascularization and skin regeneration. Reproduced with permission [28]. Copyright 2024 American Chemical Society. B. Schematic illustration of FM-Exo nanohybrids promoting diabetic wound healing. Reproduced with permission [12]. Copyright 2024, Elsevier. C. Schematic diagram of Se-CuSrHA@EGCG NPs regulating the polarization of M2-type macrophages to promote vascularized alveolar bone regeneration. Reproduced with permission [30]. Copyright 2025, Elsevier.

Fig. 2

Roles of immune cells in various stages of angiogenesis. A. Early inflammatory phase. B. Tip cell guidance and migration. C. Stalk elongation. D. Vessel maturation.

Fig. 3

A. G-TSrP multifunctional nanocomposite hydrogel enhanced the homing of M1 macrophages in the early stage and induced M2-type polarization in the later stage, promoting angiogenesis. Reproduced with permission [56]. Copyright 2024, Elsevier. B. Polarized BaTiO₃ nanofiber (BTNF)/P (VDF-TRFE) nanocomposite membranes provided heterogeneous surface potential distributions and efficiently induced the differentiation of macrophages into the M2 phenotype, thereby promoting the angiogenic differentiation of endothelial cells [67]. Copyright 2024, Wiley.

Fig. 4

NMs facilitate communication among immune cells. A. Schematic diagram of mixed biomaterials (Gel@fMLP/SiO₂-FasL) promoting M2-type macrophages through spatiotemporal regulation of neutrophil recruitment and apoptosis. Reproduced with permission [81]. Copyright 2022, Wiley-VCH GmbH. B. Immunofluorescence, flow cytometry and WB results showing that Gel@fMLP/SiO₂-FasL promotes M2 macrophage polarization through spatiotemporal regulation of neutrophil recruitment and apoptosis. Reproduced with permission [81]. Copyright 2022, Wiley-VCH GmbH. C. DC-derived small extracellular vesicles (DsEVs) can effectively activate CD4⁺ T cells, induce the activation of M2 macrophages/microglia, inhibit the expression of inflammatory cytokines, and establish a beneficial immune microenvironment. Reproduced with permission [77]. Copyright 2024, Wiley-VCH GmbH.

Fig. 5

NMs promote angiogenesis through the physical microenvironment. A. Hard polyacrylamide gels (323 kPa) polarize macrophages towards a proinflammatory phenotype with impaired phagocytosis, whereas soft (11 kPa) and moderately stiff (88 kPa) gels polarize cells towards an anti-inflammatory, highly phagocytotic phenotype. Reproduced with permission [88]. Copyright 2019, Elsevier. B. Macrophages are polarized towards the proinflammatory M1 phenotype via Piezo1-YAP on rigid substrates and towards the anti-inflammatory M2 phenotype on soft and moderately stiff substrates. Reproduced with permission [90]. Copyright 2019, Wiley. C. The thermally elastic nanohybrid 3D-TIPS scaffold exhibits “stiffness memory”, with high initial stiffness and layered porous structures superior to those of softer scaffolds, promoting macrophage M2-type polarization and guiding angiogenesis during softening. Reproduced with permission [66]. Copyright 2019, Elsevier. D. Schematic diagram of the nanoscale IEF within nanofibers mimicking the physiologically heterogeneous electrical microenvironment of the bone matrix (left). The coupling of immunomodulation and angiogenesis within a heterogeneous electric microenvironment promotes bone regeneration (middle). Calcium channel-mediated intracellular PI3K signalling cascades of macrophages promoting proangiogenic transformation (right). Reproduced with permission [96]. Copyright 2024, Wiley.

Fig. 6

NMs promote angiogenesis through the chemical microenvironment. A. pH-regulated NMs promote angiogenesis by altering the environmental pH. Reproduced with permission [106]. Copyright 2019, Elsevier. B. M-chiral nanofibers promote the influx of extracellular Ca²⁺ into the cell by activating the mechanosensitive ion channel PIEZO1, increasing nuclear translocation and STAT phosphorylation and promoting M2 polarization. Reproduced with permission [105]. Copyright 2019, Elsevier.

Fig. 7

NMs regulate membrane receptors to modulate immune cell functions to promote angiogenesis. A. CG/PHA/PBT regulates M2 macrophage polarization through the PI3K/Akt signalling axis and promotes vascularized bone regeneration [114]. Copyright 2023, BMC. B. By inducing the aggregation of mannose receptors on the cell surface, KSiNPs effectively polarize macrophages towards the M2 phenotype, thereby promoting angiogenesis. Reproduced with permission [115]. Copyright 2019, Elsevier.

Fig. 8

NMs polarize M2 macrophages by regulating gene transcription to promote angiogenesis. A. Mesoporous silica promotes histone H3 acetylation and decreases DNA methylation and H3K9 trimethylation in CD4⁺ T cells, promotes Th17 cell differentiation and IL-17A expression, and enhances angiogenesis. Reproduced with permission [7]. Copyright 2023, Wiley. B. Schematic illustration of gelatine nanomaterials loaded with exosomes containing miR-451a promoting M2-type polarization in macrophages by inhibiting MIF. Reproduced with permission [132]. Copyright 2022, BMC.

Fig. 9

NMs promote angiogenesis by regulating redox metabolism and lipid metabolism in macrophages. A. Zn-POM clears cytoplasmic reactive oxygen species such as H₂O₂ and induces the reprogramming of macrophages to the M2 phenotype by inhibiting the MAPK/IL-17 signalling pathway. Reproduced with permission [137]. Copyright 2024, BMC. B. BNP-PEDOT-PSF-AG hydrogel upregulates genes related to lipid catabolism. Reproduced with permission [151]. Copyright 2024, Nature Publishing Group.

Fig. 10

Mechanisms by which NMs regulate immune cells. NMs promote pro-angiogenic immune responses through the following ways: (A) extracellular regulation, including regulation of hardness, mechanical strain, electrical/magnetic signals, pH microenvironment to induce immune cells to polarize towards the angiogenic phenotype; (B) cell membrane interaction, by activating membrane receptors (such as TLR4, integrins, PIEZO1), lipid raft aggregation, and regulation of membrane potential to initiate downstream signal transduction; and (C) intracellular regulation, involving control of oxidative stress (ROS), metabolism (redox metabolism, lipid metabolism, and amino acid metabolism), gene transcription (such as through miRNA), and autophagy to reprogram the phenotype of immune cells and enable them to have the function of promoting angiogenesis.

Fig. 11

The immunoangiogenesis properties of nanomaterials.