Therapeutic intervention in neuroinflammation for neovascular ocular diseases through targeting the cGAS-STING-necroptosis pathway.

The microglia-mediated neuroinflammation have been shown to play a crucial role in the ocular pathological angiogenesis process, but specific immunotherapies for neovascular ocular diseases are still lacking. This study proposed that targeting GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) might be a novel immunotherapy for these angiogenesis diseases. We found a significant upregulation of CGAS and STING genes in the RNA-seq data derived from retinal tissues of the patients with proliferative diabetic retinopathy. In experimental models of ocular angiogenesis including laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), the cGAS-STING pathway was activated as angiogenesis progressed. Either genetic deletion or pharmacological inhibition of STING resulted in a remarkable suppression of neovascularization in both models. Furthermore, cGAS-STING signaling was specifically activated in myeloid cells, triggering the subsequent RIP1-RIP3-MLKL pathway activation and leading to necroptosis-mediated inflammation. Notably, targeted inhibition of the cGAS-STING pathway with C-176 or SN-011 could significantly suppress pathological angiogenesis in CNV and OIR. Additionally, the combination of C-176 or SN-011 with anti-VEGF therapy led to least angiogenesis, markedly enhancing the anti-angiogenic effectiveness. Together, our findings provide compelling evidence for the importance of the cGAS-STING-necroptosis axis in pathological angiogenesis, highlighting its potential as a promising immunotherapeutic target for treating neovascular ocular diseases.

Decreasing mitochondrial fission ameliorates HIF-1α-dependent pathological retinal angiogenesis.

Angiogenesis plays a critical role in many pathological processes, including irreversible blindness in eye diseases such as retinopathy of prematurity. Endothelial mitochondria are dynamic organelles that undergo constant fusion and fission and are critical signalling hubs that modulate angiogenesis by coordinating reactive oxygen species (ROS) production and calcium signalling and metabolism. In this study, we investigated the role of mitochondrial dynamics in pathological retinal angiogenesis. We showed that treatment with vascular endothelial growth factor (VEGF; 20 ng/ml) induced mitochondrial fission in HUVECs by promoting the phosphorylation of dynamin-related protein 1 (DRP1). DRP1 knockdown or pretreatment with the DRP1 inhibitor Mdivi-1 (5 µM) blocked VEGF-induced cell migration, proliferation, and tube formation in HUVECs. We demonstrated that VEGF treatment increased mitochondrial ROS production in HUVECs, which was necessary for HIF-1α-dependent glycolysis, as well as proliferation, migration, and tube formation, and the inhibition of mitochondrial fission prevented VEGF-induced mitochondrial ROS production. In an oxygen-induced retinopathy (OIR) mouse model, we found that active DRP1 was highly expressed in endothelial cells in neovascular tufts. The administration of Mdivi-1 (10 mg·kg-1·d-1, i.p.) for three days from postnatal day (P) 13 until P15 significantly alleviated pathological angiogenesis in the retina. Our results suggest that targeting mitochondrial fission may be a therapeutic strategy for proliferative retinopathies and other diseases that are dependent on pathological angiogenesis.

RNA binding protein ELAVL1-mediated USP33 stabilizes HIF1A to promote pathological proliferation, migration and angiogenesis of RECs.

BACKGROUND: Dysfunction of retinal vascularization plays pathogenic roles in retinopathy of prematurity (ROP). Hypoxia-inducible factor 1 alpha (HIF1A) is activated by hypoxia and contributes to ROP progression. Herein, we clarified the mechanism underlying HIF1A activation in human retinal vascular endothelial cells (HRECs) under hypoxia. METHODS: Protein expression was assayed by immunoblot analysis. Cell migration, microtubule formation, invasion, proliferation, and viability were detected by wound-healing, tube formation, transwell, EdU, and CCK-8 assays, respectively. Bioinformatics was used to predict the deubiquitinase-HIF1A interactions and RNA binding proteins (RBPs) bound to USP33. The impact of USP33 on HIF1A deubiquitination was validated by immunoprecipitation (IP) assay. RNA stability analysis was performed with actinomycin D (Act D) treatment. The ELAVL1/USP33 interaction was assessed by RNA immunoprecipitation experiment. RESULTS: In hypoxia-exposed HRECs, HIF1A and USP33 protein levels were upregulated. Deficiency of HIF1A or USP33 suppressed cell migration, proliferation and microtubule formation of hypoxia-exposed HRECs. Mechanistically, USP33 deficiency led to an elevation in HIF1A ubiquitination and degradation. USP33 deficiency reduced HIF1A protein levels to suppress the proliferation and microtubule formation of hypoxia-induced HRECs. Moreover, the RBP ELAVL1 stabilized USP33 mRNA to increase USP33 protein levels. ELAVL1 decrease repressed the proliferation and microtubule formation of hypoxia-induced HRECs by reducing USP33. CONCLUSION: Our study identifies a novel ELAVL1/USP33/HIF1A regulatory cascade with the ability to affect hypoxia-induced pathological proliferation, angiogenesis, and migration in HRECs.

Calpain-mediated proteolytic production of free amino acids in vascular endothelial cells augments obesity-induced hepatic steatosis.

Free amino acids that accumulate in the plasma of patients with diabetes and obesity influence lipid metabolism and protein synthesis in the liver. The stress-inducible intracellular protease calpain proteolyzes various substrates in vascular endothelial cells (ECs), although its contribution to the supply of free amino acids in the liver microenvironment remains enigmatic. In the present study, we showed that calpains are associated with free amino acid production in cultured ECs. Furthermore, conditioned media derived from calpain-activated ECs facilitated the phosphorylation of ribosomal protein S6 kinase (S6K) and de novo lipogenesis in hepatocytes, which were abolished by the amino acid transporter inhibitor, JPH203, and the mammalian target of rapamycin complex 1 inhibitor, rapamycin. Meanwhile, calpain-overexpressing capillary-like ECs were observed in the livers of high-fat diet-fed mice. Conditional KO of EC/hematopoietic Capns1, which encodes a calpain regulatory subunit, diminished levels of branched-chain amino acids in the hepatic microenvironment without altering plasma amino acid levels. Concomitantly, conditional KO of Capns1 mitigated hepatic steatosis without normalizing body weight and the plasma lipoprotein profile in an amino acid transporter-dependent manner. Mice with targeted Capns1 KO exhibited reduced phosphorylation of S6K and maturation of lipogenic factor sterol regulatory element-binding protein 1 in hepatocytes. Finally, we show that bone marrow transplantation negated the contribution of hematopoietic calpain systems. We conclude that overactivation of calpain systems may be responsible for the production of free amino acids in ECs, which may be sufficient to potentiate S6K/sterol regulatory element-binding protein 1-induced lipogenesis in surrounding hepatocytes.

NF-κB: a mediator that promotes or inhibits angiogenesis in human diseases?

The nuclear factor of κ-light chain of enhancer-activated B cells (NF-κB) signaling pathway, which is conserved in invertebrates, plays a significant role in human diseases such as inflammation-related diseases and carcinogenesis. Angiogenesis refers to the growth of new capillary vessels derived from already existing capillaries and postcapillary venules. Maintaining normal angiogenesis and effective vascular function is a prerequisite for the stability of organ tissue function, and abnormal angiogenesis often leads to a variety of diseases. It has been suggested that NK-κB signalling molecules under pathological conditions play an important role in vascular differentiation, proliferation, apoptosis and tumourigenesis by regulating the transcription of multiple target genes. Many NF-κB inhibitors are being tested in clinical trials for cancer treatment and their effect on angiogenesis is summarised. In this review, we will summarise the role of NF-κB signalling in various neovascular diseases, especially in tumours, and explore whether NF-κB can be used as an attack target or activation medium to inhibit tumour angiogenesis.

ADAMTS5 promotes neovascularization via autophagic degradation of PEDF in proliferative diabetic retinopathy.

Proliferative diabetic retinopathy (PDR) adversely affects visual function. Extracellular matrix proteins (ECM) contribute significantly to the development of PDR. A Disintegrin and Metalloproteinase with Thrombospondin motifs 5 (ADAMTS5) is a member of ECM proteins. ADAMTS5 participates in angiogenesis and inflammation in diverse diseases. However, the role of ADAMTS5 in PDR remains elusive. Multiplex beam array technology was used to analyze vitreous humor of PDR patients and normal people. ELISA and Western blot were used to detect the expression of ADAMTS5, PEDF and autophagy related factors. Immunofluorescence assay was used to mark the expression and localization of ADAMTS5 and PEDF. The neovascularization was detected by tube formation test. Our results revealed that ADAMTS5 expression was increased in the vitreous humor of PDR patients and oxygen-induced retinopathy (OIR) mice retinas. Inhibiting ADAMTS5 alleviated pathological angiogenesis and upregulated PEDF expression in the OIR mice. In addition, ADAMTS5 inhibited PEDF secretion in ARPE-19 cells in vitro studies, thereby inhibiting the migration of HMEC-1. Mechanically, ADAMTS5 promoted the autophagic degradation of PEDF. Collectively, inhibition of ADAMTS5 during OIR suppresses pathological angiogenesis. Our study provides a new approach for resolving pathological angiogenesis in PDR.

Targeting circular RNA-MET for anti-angiogenesis treatment via inhibiting endothelial tip cell specialization.

Endothelial tip cell specialization plays an essential role in angiogenesis, which is tightly regulated by the complicated gene regulatory network. Circular RNA (circRNA) is a type of covalently closed non-coding RNA that regulates gene expression in eukaryotes. Here, we report that the levels of circMET expression are significantly upregulated in the retinas of mice with oxygen-induced retinopathy, choroidal neovascularization, and diabetic retinopathy. circMET silencing significantly reduces pathological angiogenesis and inhibits tip cell specialization in vivo. circMET silencing also decreases endothelial migration and sprouting in vitro. Mechanistically, circMET regulates endothelial sprouting and pathological angiogenesis by acting as a scaffold to enhance the interaction between IGF2BP2 and NRARP/ESM1. Clinically, circMET is significantly upregulated in the clinical samples of the patients of diabetic retinopathy. circMET silencing could reduce diabetic vitreous-induced endothelial sprouting and retinal angiogenesis in vivo. Collectively, these data identify a circRNA-mediated mechanism that coordinates tip cell specialization and pathological angiogenesis. circMET silencing is an exploitable therapeutic approach for the treatment of neovascular diseases.

Secretogranin III stringently regulates pathological but not physiological angiogenesis in oxygen-induced retinopathy.

Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized Scg3 binding exclusively to disease-related disorganized retinal neovessels and neovascular tufts, whereas VEGF bound to both disorganized and well-organized neovessels. Homozygous deletion of the Scg3 gene showed undetectable effects on physiological retinal neovascularization but markedly reduced the severity of OIR-induced pathological angiogenesis. Furthermore, anti-Scg3 humanized antibody Fab (hFab) inhibited pathological angiogenesis with similar efficacy to anti-VEGF aflibercept. Aflibercept dose-dependently blocked physiological angiogenesis in neonatal retinas, whereas anti-Scg3 hFab was without adverse effects at any dose and supported a therapeutic window at least 10X wider than that of aflibercept. Therefore, Scg3 stringently regulates pathological but not physiological angiogenesis, and anti-Scg3 hFab satisfies essential criteria for development as a safe and effective disease-targeted anti-angiogenic therapy for ROP.

Harnessing retinal phagocytes to combat pathological neovascularization in ischemic retinopathies?

Ischemic retinopathies (IR) are vision-threatening diseases that affect a substantial amount of people across all age groups worldwide. The current treatment options of photocoagulation and anti-VEGF therapy have side effects and are occasionally unable to prevent disease progression. It is therefore worthwhile to consider other molecular targets for the development of novel treatment strategies that could be safer and more efficient. During the manifestation of IR, the retina, normally an immune privileged tissue, encounters enhanced levels of cellular stress and inflammation that attract mononuclear phagocytes (MPs) from the blood stream and activate resident MPs (microglia). Activated MPs have a multitude of effects within the retinal tissue and have the potential to both counter and exacerbate the harmful tissue microenvironment. The present review discusses the current knowledge about the role of inflammation and activated retinal MPs in the major IRs: retinopathy of prematurity and diabetic retinopathy. We focus particularly on MPs and their secreted factors and cell-cell-based interactions between MPs and endothelial cells. We conclude that activated MPs play a major role in the manifestation and progression of IRs and could therefore become a promising new target for novel pharmacological intervention strategies in these diseases.

Studying molecular signaling in major angiogenic diseases.

The growth of blood vessels from already existing vasculature is angiogenesis and it is one of the fundamental processes in fetal development, tissue damage or repair, and the reproductive cycle. In a healthy person, angiogenesis is regulated by the balance between pro- and anti-angiogenic factors. However, when the balance is disturbed, it results in various diseases or disorders. The angiogenesis pathway is a sequential cascade and differs based on the stimuli. Therefore, targeting one of the factors involved in the process can help us find a therapeutic strategy to treat irregular angiogenesis. In the past three decades of cancer research, angiogenesis has been at its peak, where an anti-angiogenic agent inhibiting vascular endothelial growth factor acts as a promising substance to treat cancer. In addition, cancer can be assessed based on the expression of angiogenic factors and its response to therapies. Angiogenesis is important for all tissues, which might be normal or pathologically changed and occur through ages. In clinical therapeutics, target therapy focusing on discovery of novel anti-angiogenic agents like bevacizumab, cetuximab, sunitinib, imatinib, lenvatinib, thalidomide, everolimus etc., to block or inhibit the angiogenesis pathway is well explored in recent times. In this review, we will discuss about the molecular signaling pathways involved in major angiogenic diseases in detail.

Recombinant thrombomodulin domain 1 rescues pathological angiogenesis by inhibition of HIF-1α-VEGF pathway.

Pathological angiogenesis (PA) contributes to various ocular diseases, including age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity, which are major causes of blindness over the world. Current treatments focus on anti-vascular endothelial growth factor (VEGF) therapy, but persistent avascular retina, recurrent intravitreal neovascularization, and general adverse effects are reported. We have previously found that recombinant thrombomodulin domain 1 (rTMD1) can suppress vascular inflammation. However, the function of rTMD1 in VEGF-induced PA remains unknown. In this study, we found that rTMD1 inhibited VEGF-induced angiogenesis in vitro. In an oxygen induced retinopathy (OIR) animal model, rTMD1 treatment significantly decreased retinal neovascularization but spared normal physiological vessel growth. Furthermore, loss of TMD1 significantly promoted PA in OIR. Meanwhile, hypoxia-inducible factor-1α, the transcription factor that upregulates VEGF, was suppressed after rTMD1 treatment. The levels of interleukin-6, and intercellular adhesion molecule-1 were also significantly suppressed. In conclusion, our results indicate that rTMD1 not only has dual effects to suppress PA and inflammation in OIR, but also can be a potential HIF-1α inhibitor for clinical use. These data bring forth the possibility of rTMD1 as a novel therapeutic agent for PA.

MicroRNA-150 (miR-150) and Diabetic Retinopathy: Is miR-150 Only a Biomarker or Does It Contribute to Disease Progression?

Diabetic retinopathy (DR) is a chronic disease associated with diabetes mellitus and is a leading cause of visual impairment among the working population in the US. Clinically, DR has been diagnosed and treated as a vascular complication, but it adversely impacts both neural retina and retinal vasculature. Degeneration of retinal neurons and microvasculature manifests in the diabetic retina and early stages of DR. Retinal photoreceptors undergo apoptosis shortly after the onset of diabetes, which contributes to the retinal dysfunction and microvascular complications leading to vision impairment. Chronic inflammation is a hallmark of diabetes and a contributor to cell apoptosis, and retinal photoreceptors are a major source of intraocular inflammation that contributes to vascular abnormalities in diabetes. As the levels of microRNAs (miRs) are changed in the plasma and vitreous of diabetic patients, miRs have been suggested as biomarkers to determine the progression of diabetic ocular diseases, including DR. However, few miRs have been thoroughly investigated as contributors to the pathogenesis of DR. Among these miRs, miR-150 is downregulated in diabetic patients and is an endogenous suppressor of inflammation, apoptosis, and pathological angiogenesis. In this review, how miR-150 and its downstream targets contribute to diabetes-associated retinal degeneration and pathological angiogenesis in DR are discussed. Currently, there is no effective treatment to stop or reverse diabetes-caused neural and vascular degeneration in the retina. Understanding the molecular mechanism of the pathogenesis of DR may shed light for the future development of more effective treatments for DR and other diabetes-associated ocular diseases.

Concurrent Physiological and Pathological Angiogenesis in Retinopathy of Prematurity and Emerging Therapies.

Retinopathy of prematurity (ROP) is an ocular vascular disease affecting premature infants, characterized by pathological retinal neovascularization (RNV), dilated and tortuous retinal blood vessels, and retinal or vitreous hemorrhages that may lead to retinal detachment, vision impairment and blindness. Compared with other neovascular diseases, ROP is unique because of ongoing and concurrent physiological and pathological angiogenesis in the developing retina. While the disease is currently treated by laser or cryotherapy, anti-vascular endothelial growth factor (VEGF) agents have been extensively investigated but are not approved in the U.S. because of safety concerns that they negatively interfere with physiological angiogenesis of the developing retina. An ideal therapeutic strategy would selectively inhibit pathological but not physiological angiogenesis. Our group recently described a novel strategy that selectively and safely alleviates pathological RNV in animal models of ROP by targeting secretogranin III (Scg3), a disease-restricted angiogenic factor. The preclinical profile of anti-Scg3 therapy presents a high potential for next-generation disease-targeted anti-angiogenic therapy for the ROP indication. This review focuses on retinal vessel development in neonates, the pathogenesis of ROP and its underlying molecular mechanisms, including different animal models, and provides a summary of current and emerging therapies.

FTO regulates ocular angiogenesis via m6A-YTHDF2-dependent mechanism.

Pathological ocular angiogenesis commonly results in visual impairment or even blindness. Unveiling the mechanisms of pathological angiogenesis is critical to identify the regulators and develop effective targeted therapies. Here, we used corneal neovascularization (CNV) model to investigate the mechanism of pathological ocular angiogenesis. We show that N6-methyladenosine (m6A) mRNA demethylation mediated by fat mass- and obesity-associated protein (FTO) could regulate endothelial cell (EC) function and pathological angiogenesis during CNV. FTO levels are increased in neovascularized corneas and ECs under pathological conditions. In vitro silencing of FTO in ECs results in reduced cellular proliferation, migration, and tube formation under both basal and pathological conditions. Furthermore, FTO silencing attenuates suture-induced CNV in vivo. Mechanically, FTO silencing in ECs could increase m6A methylation levels in critical pro-angiogenic genes, such as FAK, leading to decreased RNA stability and increased RNA decay through m6A reader YTHDF2. Our study demonstrates that FTO regulates pathological ocular angiogenesis by controlling EC function in an m6A-YTHDF2-dependent manner.

Pericytes in the Gut.

This review chapter describes the current knowledge about the nature of pericytes in the gut, their interaction with endothelial cells in blood vessels, and their pathophysiological functions in the setting of chronic liver disease. In particular, it focuses on the role of these vascular cell types and related molecular signaling pathways in pathological angiogenesis associated with liver disease and in the establishment of the gut-vascular barrier and the potential implications in liver disease through the gut-liver axis.

N-Acetylcysteine Suppresses LPS-Induced Pathological Angiogenesis.

BACKGROUND/AIMS: Angiogenesis is a key feature during embryo development but is also part of the pathogenesis of cancer in adult life. Angiogenesis might be modulated by inflammation. METHODS: We established an angiogenesis model in chick chorioallantoic membrane (CAM) induced by the exposure of lipopolysaccharide (LPS), and analyzed the effects of the antioxidant N-acetylcysteine (NAC) on angiogenesis in this model as well as on the expression of key genes known to involved in the regulation of angiogenesis. RESULTS: Treatment with NAC was able to normalize LPS induced angiogenesis and restore the LPS-induced damage of vascular epithelium in chick CAM. Using quantitative PCR, we showed that NAC administration normalized the LPS induced expression of Keap1-Nrf2 signaling and oxidative stress key enzyme gene expressions (SOD, GPx and YAP1). CONCLUSION: We established a LPS-induced angiogenesis model in chick CAM. NAC administration could effectively inhibit LPS-induced angiogenesis and restore the integrity of endothelium on chick CAM. LPS exposure caused an increased expression of genes involved in oxidative stress in chick CAM. NAC administration could abolish this effect.

Anti-angiogenic effects of valproic acid in a mouse model of oxygen-induced retinopathy.

Pathological retinal angiogenesis contributes to the pathogenesis of several ocular diseases. Valproic acid, a widely used antiepileptic drug, exerts anti-angiogenic effects by inhibiting histone deacetylase (HDAC). Herein, we investigated the effects of valproic acid and vorinostat, a HDAC inhibitor, on pathological retinal angiogenesis in mice with oxygen-induced retinopathy (OIR). OIR was induced in neonatal mice by exposure to 80% oxygen from postnatal day (P) 7 to P10 and to atmospheric oxygen from P10 to P15. Mice were subcutaneously injected with valproic acid, vorinostat, or vehicle once a day from P10 to P14. At P15, retinal neovascular tufts and vascular growth in the central avascular zone were observed in mice with OIR. Additionally, immunoreactivity for phosphorylated ribosomal protein S6 (pS6), an indicator of mammalian target of rapamycin (mTOR) activity, was detected in the neovascular tufts. Both valproic acid and vorinostat reduced the formation of retinal neovascular tuft without affecting vascular growth in the central avascular zone. Valproic acid reduced the pS6 immunoreactivity in neovascular tufts. Given that vascular endothelial growth factor (VEGF) activates mTOR-dependent pathways in proliferating endothelial cells of the neonatal mouse retina, these results suggest that valproic acid suppresses pathological retinal angiogenesis by interrupting VEGF-mTOR pathways.

Mammalian Target of Rapamycin (mTOR) as a Potential Therapeutic Target in Pathological Ocular Angiogenesis.

Pathological ocular angiogenesis is a causative factor of retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. Vascular endothelial growth factor (VEGF) plays an important role in pathological angiogenesis, and anti-VEGF agents have been used to treat the ocular diseases that are driven by pathological angiogenesis. However, adverse effects associated with the blockade of VEGF signaling, including impairments of normal retinal vascular growth and retinal function, were suggested. Therefore, the development of a safe, effective strategy to prevent pathological ocular angiogenesis is needed. Recent studies have demonstrated that inhibitors of the mammalian target of rapamycin (mTOR) target proliferating endothelial cells within the retinal vasculature. Here, we review the potential of targeting the mTOR pathway to treat pathological ocular angiogenesis.

Non-Coding RNAs: Novel Regulators of Macrophage Homeostasis in Ocular Vascular Diseases.

Ocular neovascularization can impair vision and threaten patients' quality of life. However, the underlying mechanism is far from transparent. In all mammals, macrophages are a population of cells playing pivotal roles in the innate immune system and the first line of defense against pathogens. Therefore, it has been speculated that the disfunction of macrophage homeostasis is involved in the development of ocular vascular diseases. Moreover, various studies have found that non-coding RNAs (ncRNAs) regulate macrophage homeostasis. This study reviewed past studies of the regulatory roles of ncRNAs in macrophage homeostasis in ocular vascular diseases.

Iron Oxide Nanoparticles Engineered Macrophage-Derived Exosomes for Targeted Pathological Angiogenesis Therapy.

Engineering exosomes with nanomaterials usually leads to the damage of exosomal membrane and bioactive molecules. Here, pathological angiogenesis targeting exosomes with magnetic imaging, ferroptosis inducing, and immunotherapeutic properties is fabricated using a simple coincubation method with macrophages being the bioreactor. Extremely small iron oxide nanoparticle (ESIONPs) incorporated exosomes (ESIONPs@EXO) are acquired by sorting the secreted exosomes from M1-polarized macrophages induced by ESIONPs. ESIONPs@EXO suppress pathological angiogenesis in vitro and in vivo without toxicity. Furthermore, ESIONPs@EXO target pathological angiogenesis and exhibit an excellent T1-weighted contrast property for magnetic resonance imaging. Mechanistically, ESIONPs@EXO induce ferroptosis and exhibit immunotherapeutic ability toward pathological angiogenesis. These findings demonstrate that a pure biological method engineered ESIONPs@EXO using macrophages shows potential for targeted pathological angiogenesis therapy.