Chemical composition and anti-angiogenic activity of the essential oil from Blumea eriantha D.C.

Blumea eriantha D.C is a weed from Asteraceae family and is reported to have anticancer activity. The essential oil from the aerial parts was extracted by steam distillation method with the yield of 0.36%. Through GC-MS analysis of the oil, seventeen compounds could be identified by comparing with linear retention indices with the library. Out of the seventeen compounds ß-Caryophylline oxide was isolated by column chromatography with gradient elution and the structure was determined through FT-IR, MS, 1HNMR, 13 C NMR and DEPT. The oil was evaluated for its effect on angiogenesis using Chorioallantoic Membrane Assay (CAM Assay). The concentration dependent antiangiogenic effect was observed with IC 50 value of 19.28 ppm.

Pre-coating cRGD-modified bovine serum albumin enhanced the anti-tumor angiogenesis of siVEGF-loaded chitosan-based nanoparticles by manipulating the protein corona composition.

Chitosan-based nanoparticles inevitably adsorb numerous proteins in the bloodstream, forming a protein corona that significantly influences their functionality. This study employed a pre-coated protein corona using cyclic Arg-Gly-Asp peptide (cRGD)-modified bovine serum albumin (BcR) to confer tumor-targeting capabilities on siVEGF-loaded chitosan-based nanoparticles (CsR/siVEGF NPs) and actively manipulated the serum protein corona composition to enhance their anti-tumor angiogenesis. Consequently, BcR effectively binds to the nanoparticles' surface, generating nanocarriers of appropriate size and stability that enhance the inhibition of endothelial cell proliferation, migration, invasion, and tube formation, as well as suppress tumor proliferation and angiogenesis in tumor-bearing nude mice. Proteomic analysis indicated a significant enrichment of serotransferrin, albumin, and proteasome subunit alpha type-1 in the protein corona of BcR-precoated NPs formed in the serum of tumor-bearing nude mice. Additionally, there was a decrease in proteins associated with complement activation, immunoglobulins, blood coagulation, and acute-phase responses. This modification resulted in an enhanced impact on anti-tumor angiogenesis, along with a reduction in opsonization and inflammatory responses. Therefore, pre-coating of nanoparticles with a functionalized albumin corona to manipulate the composition of serum protein corona emerges as an innovative approach to improve the delivery effectiveness of chitosan-based carriers for siVEGF, targeting the inhibition of tumor angiogenesis.

An antitumor fungal polysaccharide from Fomitopsis officinalis by activating immunity and inhibiting angiogenesis.

Macrofungi, a class of unique natural resources, are gaining popularity owing to their potential therapeutic benefits and edibility. From Fomitopsis officinalis, a medicinal macrofungus with anticancer activity, a homogeneous heteropolysaccharide (FOBP50-1) with a molecular weight of 2.21 × 104 g/mol has been extracted and purified. FOBP50-1 was found to be composed of 3-O-methylfucose, fucose, mannose, glucose, and galactose with a ratio of 1: 6.5: 4.4: 8.1: 18.2. The sugar fragments and structure of FOBP50-1 were investigated, which included →6)-α-d-Galp-(1→, →2,6)-α-d-Galp-(1→, →3)-α-l-Fucp-(1→, α-d-Glcp-(1→, →3)-ß-d-Manp-(1→, →6)-ß-d-Manp-(1→, 3-O-Me-α-l-Fucp-(1→, according to the UV, FT-IR, GC-MS, and NMR data. Besides the structure elucidation, FOBP50-1 showed promising antitumor activity in the zebrafish assays. The following mechanism examination discovered that FOBP50-1 interacted with TLR-4, PD-1, and VEGF to activate immunity and inhibit angiogenesis according to a series of cell, transgenic zebrafish, and surface plasmon resonance (SPR) experiments. The KD values indicating the association of FOBP50-1 with TLR-4, PD-1, and VEGF, were 4.69 × 10-5, 7.98 × 10-6, 3.04 × 10-6 M, respectively, in the SPR experiments. All investigations have demonstrated that the homogenous fungal polysaccharide FOBP50-1 has the potential to be turned into a tumor immunotherapy agent.

Neuropilin-1-Targeted Nanomedicine for Spatiotemporal Tumor Suppression through Photodynamic Vascular Damage and Antiangiogenesis.

Antiangiogenic therapy is an effective way to disrupt nutrient supply and starve tumors, but it is restricted by poor efficacy and negative feedback-induced tumor relapse. In this study, a neuropilin-1 (NRP-1)-targeted nanomedicine (designated as FPPT@Axi) is reported for spatiotemporal tumor suppression by combining photodynamic therapy (PDT) with antiangiogenesis. In brief, FPPT@Axi is prepared by utilizing an NRP-1-targeting chimeric peptide (Fmoc-K(PpIX)-PEG8-TKPRR) to encapsulate the antiangiogenic drug Axitinib (Axi). Importantly, the NRP-1-mediated targeting property enables FPPT@Axi to selectively concentrate at vascular endothelial and breast cancer cells, facilitating the production of reactive oxygen species (ROS) in situ for specific vascular disruption and enhanced cell apoptosis under light stimulation. Moreover, the codelivered Axi can further inhibit vascular endothelial growth factor receptor (VEGFR) to impair the negative feedback of PDT-induced tumor neovascularization. Consequently, FPPT@Axi spatiotemporally restrains the tumor growth through blocking angiogenesis, destroying tumor vessels, and inducing tumor apoptosis. Such an NRP-1-mediated targeting codelivery system sheds light on constructing an appealing candidate with translational potential by using clinically approved PDT and chemotherapy.

Arene-Arene Coupled Disulfamethazines (or Sulfadiazine)-Phenanthroline-Metal(II) Complexes were Synthesized by In Situ Reactions and Inhibited the Growth and Development of Triple-Negative Breast Cancer through the Synergistic Effect of Antiangiogenesis, Anti-Inflammation, Pro-Apoptosis, and Cuproptosis.

The novel metal(II)-based complexes HA-Cu, HA-Co, and HA-Ni with phenanthroline, sulfamethazine, and aromatic-aromatic coupled disulfamethazines as ligands were synthesized and characterized. HA-Cu, HA-Co, and HA-Ni all showed a broad spectrum of cytotoxicity and antiangiogenesis. HA-Cu was superior to HA-Co and HA-Ni, and even superior to DDP, showing significant inhibitory effect on the growth and development of tripe-negative breast cancer in vivo and in vitro. HA-Cu exhibited observable synergistic effects of antiproliferation, antiangiogenesis, anti-inflammatory, pro-apoptosis, and cuproptosis to effectively inhibited tumor survival and development. The molecular mechanism was confirmed that HA-Cu could downregulate the expression of key proteins in the VEGF/VEGFR2 signaling pathway and the expression of inflammatory cytokines, enhance the advantage of pro-apoptotic protein Bax, and enforce cuproptosis by weakening the expression of FDX1 and enhancing the expression of HSP70. Our research will provide a theoretical and practical reference for the development of metal-sulfamethazine and its derivatives as chemotherapy drugs for cancer treatment.

Peptidylarginine Deiminases Inhibitors Decrease Endothelial Cells Angiogenic Potential by Affecting Akt Signaling and the Expression and Secretion of Angiogenic Factors.

BACKGROUND/AIMS: Endothelial cells (ECs) play a crucial role in various physiological processes, particularly those related to the cardiovascular system, but also those affecting the entire organism. The biology of ECs is regulated by multiple biochemical stimuli and epigenetic drivers that govern gene expression. We investigated the angiogenic potential of ECs from a protein citrullination perspective, regulated by peptidyl-arginine deiminases (PADs) that modify histone and non-histone proteins. Although the involvement of PADs has been demonstrated in several physiological processes, inflammation-related disorders and cancer, their role in angiogenesis remains unclear. METHODS: To elucidate the role of PADs in endothelial angiogenesis, we used two human EC models: primary vein (HUVECs) and microvascular endothelial cells (HMEC-1). PADs activity was inhibited using irreversible inhibitors: BB-Cl-amidine, Cl-amidine and F-amidine. We analyzed all three steps of angiogenesis in vitro : proliferation, migration, and capillary-like tube formation, as well as secretory activities, gene expression and signaling in ECs. RESULTS: All used PAD inhibitors reduced the histone H3 citrullination (H3cit) mark, inhibited endothelial cell migration and capillary-like tube formation, and favored an angiostatic activity in HMEC-1 cells, by increasing PEDF (pigment epithelium-derived factor) and reducing VEGF (vascular endothelial growth factor) mRNA expression and protein secretion. Additionally, BB-Cl-amidine reduced the total activity of MMPs (Matrix metalloproteinases). The observed effects were underlined by the inhibition of Akt phosphorylation.>. CONCLUSION: Our findings suggest that pharmacological inhibitors of citrullination are promising therapeutic agents to target angiogenesis.

FS145, the first flea-derived disintegrin, inhibits angiogenesis through specifically binding integrin αvß3.

FS145, a protein containing a WGD motif, was previously described from the salivary transcriptome of the flea Xenopsylla cheopis. Nevertheless, its biological function and complete structure are still uncertain. Herein, FS145 was confirmed to adopt a common αßß structure with the WGD motif exposed on its surface and located right at the top of a loop composed of residues 72-81. Furthermore, FS145 dose-dependently inhibited the proliferation, adhesion, migration, and tube formation of HUVECs by not only binding to integrin αvß3 but also by subsequently inactivating the FAK/Src/MAPK pathway along with the reduction of the expression of MMP-2, MMP-9, VEGFA, bFGF, Ang2, Tie2, HIF-1α, and FAK. Moreover, FS145 also inhibited aortic vessel sprout and showed strong anti-angiogenic activities as assessed ex vivo, by employing the rat aortic ring assay, chick embryo chorioallantoic membrane, and zebrafish embryo models. Altogether, our results suggest that FS145 suppresses angiogenesis ex vivo and in vitro by blocking integrin αvß3. The current study reveals the first anti-angiogenesis disintegrin with WGD motif from invertebrates and provides a beneficial pharmacological activity to inhibit abnormal angiogenesis.

Indoloquinazoline alkaloids suppress angiogenesis and inhibit metastasis of melanoma cells.

Metastasis is the leading cause of cancer-related mortality, targeting angiogenesis emerges as a therapeutic strategy for the treatment of melanoma metastasis. Discovery of new antiangiogenic compounds with specific mechanism of action is still desired. In present study, a bioassay-guidance uncovers the EtOAc extract of a marine-derived fungus Aspergillus clavutus LZD32-24 with significant inhibitory activity against the angiogenesis in Tg (fli1a: EGFP) zebrafish model. Extensive chromatographic fractionation led to the isolation of 48 indoloquinazoline alkaloids, including 21 new analogues namely clavutoines A-U (1-21). Their structures were determined by the spectroscopic data, including the ECD, single crystal X-ray diffraction and quantum chemical calculation for the configurational assignments. Among the bioactive analogues, quinadoline B (QB) showed the most efficacy to suppress the zebrafish vascular outgrowth in zebrafish embryos. QB markedly inhibited the migration, invasion and tube formation with weak cytotoxicity in human umbilical vein endothelial cells (HUVECs). Investigation of the mode of action revealed QB suppressed the ROCK/MYPT1/MLC2/coffin and FAK /Src signaling pathways, and subsequently disrupted actin cytoskeletal organization. In addition, QB reduced the number of new vessels sprouting from the ex vivo chick chorioallantoic membrane (CAM), and inhibited the metastasis of B16F10 melanoma cells in lung of C57BL/6 mice through suppressing angiogenesis. These findings suggest that QB is a potential lead for the development of new antiangiogenic agent to inhibit melanoma metastasis.

Dimer Peptide Ligands of Vascular Endothelial Growth Factor: Optimizing Linker Length for High Affinity and Antiangiogenic Activity.

Macromolecular ligands targeting vascular endothelial growth factor A (VEGF) to inhibit pathological angiogenesis are used in the clinic for the treatment of cancers and ocular diseases. To develop smaller ligands retaining high affinity through an avidity effect, here we design homodimer peptides targeting the two symmetrical binding sites of the VEGF homodimer. A series of 11 dimers were synthesized with flexible poly(ethylene glycol) (PEG) linkers of increasing lengths. The binding mode was determined by size exclusion chromatography, and analytical thermodynamic parameters were measured by isothermal titration calorimetry and compared to the antibody bevacizumab. The effect of linker length was qualitatively correlated to a theoretical model. With the optimal length in PEG25-dimer D6, the binding affinity was improved 40-fold compared to a monomer control, resulting in a single-digit nanomolar Kd value. Finally, we validated the benefit of the dimerization strategy by evaluating the activity of control monomers and selected dimers in cell-based assays with human umbilical vein endothelial cells (HUVECs).

Quinazoline-based VEGFR-2 inhibitors as potential anti-angiogenic agents: A contemporary perspective of SAR and molecular docking studies.

Angiogenesis, the formation of new blood vessels from the existing vasculature, is pivotal in the migration, growth, and differentiation of endothelial cells in normal physiological conditions. In various types of tumour microenvironments, dysregulated angiogenesis plays a crucial role in supplying oxygen and nutrients to cancerous cells, leading to tumour size growth. VEGFR-2 tyrosine kinase has been extensively studied as a critical regulator of angiogenesis; thus, inhibition of VEGFR-2 has been widely used for cancer treatments in recent years. Quinazoline nucleus is a privileged and versatile scaffold with a broad range of pharmacological activity, especially in the field of tyrosine kinase inhibitors with more than twenty small molecule inhibitors approved by the US Food and Drug Administration in the last two decades. As of now, the U.S. FDA has approved eleven small chemical inhibitors of VEGFR-2 for various types of malignancies, with a prime example being vandetanib, a quinazoline derivative, which is a multi targeted kinase inhibitor used for the treatment of late-stage medullary thyroid cancer. Despite of prosperous discovery and development of VEGFR-2 down regulator drugs, there still exists limitations in clinical efficacy, adverse effects, a high rate of clinical discontinuation and drug resistance. Therefore, there is an urgent need for the design and synthesis of more selective and effective inhibitors to tackle these challenges. Through the gathering of this review, we have strived to broaden the extent of our view over the entire scope of quinazoline-based VEGFR-2 inhibitors. Herein, we give an overview of the importance and advancement status of reported structures, highlighting the SAR, biological evaluations and their binding modes.

VEGFR2 Mimicking Peptide Inhibits the Proliferation of Human Umbilical Vein Endothelial Cells (Huvecs) by Blocking VEGF.

INTRODUCTION: A variety of key human physiological processes rely on angiogenesis, ranging from reproduction and fetal growth to wound healing and tissue repair. Furthermore, this process significantly contributes to tumor progression, invasion, and metastasis. As the strongest inducer of angiogenesis, Vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR) are targets of therapeutic research for blocking pathological angiogenesis. OBJECTIVE: Preventing the interaction between VEGF and VEGFR2 by a peptide is a promising strategy for developing antiangiogenic drug candidates. This study was aimed at designing and evaluating VEGF-targeting peptides using in silico and in vitro techniques. METHODS: The VEGF binding site of VEGFR2 was considered a basis for peptide design. The interaction of VEGF and all three peptides derived from VEGFR2 were analyzed using ClusPro tools. In a complex with VEGF, the peptide with a higher docking score was evaluated to confirm its stability using molecular dynamics (MD) simulation. The gene coding for the selected peptide was cloned and expressed in E. coli BL21. The bacterial cells were cultured on a large scale, and the expressed recombinant peptide was purified using Ni-NTA chromatography. Refolding of the denatured peptide was carried out by the stepwise removal of the denaturant. The reactivity of peptides was confirmed using western blotting and enzyme-linked immunosorbent assay (ELISA) assays. Finally, the inhibition potency of the peptide on human umbilical vein endothelial cells was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- 2H-tetrazolium bromide (MTT) assay. RESULTS: Among three peptides, the peptide with the best docking pose and the highest affinity for VEGF was selected for further studies. Then the stability of the peptide was confirmed over the 100 ns MD simulation. After in silico analyses, the selected peptide was presented for in vitro analysis. Expression of the selected peptide in E. coli BL21 resulted in a pure peptide with a yield of approximately 200 µg/ml. Analysis by ELISA revealed the high reactivity of the peptide with VEGF. Western blot analysis confirmed the specific reactivity of selected peptides with VEGF. The MTT assay revealed the growth inhibitory effect of the peptide on human umbilical vein endothelial cells with an IC50 value of 247.8 µM. CONCLUSION: In summary, the selected peptide demonstrated a promising inhibitory effect on human umbilical vein endothelial cells that could be a valuable anti-angiogenic candidate for further assessment. Additionally, these in silico and in vitro data provide new insights into peptide design and engineering.

Artemisinin derivative FO-ARS-123 as a novel VEGFR2 inhibitor suppresses angiogenesis, cell migration, and invasion.

Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has been considered an important strategy for cancer therapy. VEGFR2 inhibitors targeting tumor angiogenic pathways have been widely used in clinical cancer treatment. However, inherent or acquired resistance to anti-angiogenic drugs may occur and thus limit their clinical application. New VEGFR2 inhibitors are still highly demanded. The aim of this study was to investigate VEGFR2-targeted artemisinin (ARS)-type compounds for cancer treatment. Here, we reported the ARS derivative FO-ARS-123 as a novel VEGFR2 inhibitor, which displayed potent binding activity with VEGFR2 in in silico by molecular docking (pKi, 0.40 ± 0.31 nM) and in vitro by microscale thermophoresis (Kd, 1.325 ± 0.055 µM). In addition, compound FO-ARS-123 displayed a strong inhibition on cell proliferation of a broad range of cancer cells as well as suppressed cell migration and invasion. Remarkably, FO-ARS-123 exerted profound anti-angiogenesis effects in the in vitro tube formation assay and in vivo CAM assay. These results suggest that FO-ARS-123 might be a novel and promising anti-angiogenesis agent for cancer treatment.

Halogenated Flavonoid Derivatives Display Antiangiogenic Activity.

Antiangiogenic agents attenuate tumours' growth and metastases and are therefore beneficial as an adjuvant or standalone cancer regimen. Drugs with dual antiproliferative and antiangiogenic activities can achieve anticancer efficacy and overcome acquired resistance. In this study, synthetic flavones (5a,b) with reported anticancer activity, and derivatives (4b and 6a), exhibited significant inhibition of endothelial cell tube formation (40-55%, 12 h) at 1 µM, which is comparable to sunitinib (50% inhibition at 1 µM, 48 h). Flavones (4b, 5a,b and 6a) also showed 25-37% reduction in HUVECs migration at 10 µM. In a Western blotting assay, 5a and 5b subdued VEGFR2 phosphorylation by 37% and 57%, respectively, suggesting that VEGFR2 may be their main antiangiogenic target. 5b displayed the best docking fit with VEGFR2 in an in silico study, followed by 5a, emphasizing the importance of the 7-hydroxyl group accompanied by a 4-C=S for activity. Conversely, derivatives with a 4-carbonyl moiety fitted poorly into the target's binding pocket, suggesting that their antiangiogenic activity depends on a different target. This study provides valuable insight into the Structure Activity Relationships (SAR) and modes of action of halogenated flavones with VEGFR2 and highlights their therapeutic potential as antiangiogenic/anticancer lead compounds.

Identification of a Common Pharmacophore for Binding to MMP2 and RGD Integrin: Towards a Multitarget Approach to Inhibit Cancer Angiogenesis and Metastasis.

During tumor angiogenesis different growth factors, cytokines and other molecules interact closely with each other to facilitate tumor cell invasion and metastatic diffusion. The most intensively studied as molecular targets in anti-angiogenic therapies are vascular endothelial growth factor (VEGF) and related receptors, integrin receptors and matrix metalloproteinases (MMPs). Considering the poor efficacy of cancer angiogenesis monotherapies, we reasoned combining the inhibition of αvß3 and MMP2 as a multitarget approach to deliver a synergistic blockade of tumor cell migration, invasion and metastasis. Accordingly, we identified a common pharmacophore in the binding cavity of MMP2 and αvß3, demonstrating such approach with the design, synthesis and bioassays of tyrosine-derived peptidomimetics carrying the necessary functional groups to bind to key pharmacophoric elements of MMP2 and αvß3 RGD integrin.

The Role of Bioactive Compounds in Natural Products Extracted from Plants in Cancer Treatment and Their Mechanisms Related to Anticancer Effects.

Cancer is one of the greatest causes of death worldwide. With the development of surgery, radiotherapy, and medical agents, the outcomes of cancer patients have greatly improved. However, the underlying mechanisms of cancer are not yet fully understood. Recently, natural products have been proven to be beneficial for various conditions and have played important roles in the development of novel therapies. A substantial amount of evidence indicates that bioactive compounds could improve the outcomes of cancer patients via various pathways, such as endoplasmic reticulum stress, epigenetic modification, and modulation of oxidative stress. Here, we review the current evidence of bioactive compounds in natural products for the treatment of cancer and summarize the underlying mechanisms in this pathological process.

Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors.

The screened compound DYT-1 from our in-house library was taken as a lead (inhibiting tubulin polymerisation: IC50=25.6 µM, anti-angiogenesis in Zebrafish: IC50=38.4 µM, anti-proliferation against K562 and Jurkat: IC50=6.2 and 7.9 µM, respectively). Further investigation of medicinal chemistry conditions yielded compound 29e (inhibiting tubulin polymerisation: IC50=4.8 µM and anti-angiogenesis in Zebrafish: IC50=3.6 µM) based on tubulin and zebrafish assays, which displayed noteworthily nanomolar potency against a variety of leukaemia cell lines (IC50= 0.09-1.22 µM), especially K562 cells where apoptosis was induced. Molecular docking, molecular dynamics (MD) simulation, radioligand binding assay and cellular microtubule networks disruption results showed that 29e stably binds to the tubulin colchicine site. 29e significantly inhibited HUVEC tube formation, migration and invasion in vitro. Anti-angiogenesis in vivo was confirmed by zebrafish xenograft. 29e also prominently blocked K562 cell proliferation and metastasis in blood vessels and surrounding tissues of the zebrafish xenograft model. Together with promising physicochemical property and metabolic stability, 29e could be considered an effective anti-angiogenesis and -leukaemia drug candidate that binds to the tubulin colchicine site.

Relieving immunosuppression by Endo@PLT targeting anti-angiogenesis to improve the efficacy of immunotherapies.

Low levels of immune infiltrates in the tumor milieu hinder the effectiveness of immunotherapy against immune-cold tumors. In the current work, a tumor-targeting drug delivery system composed of Endo-loaded platelets (Endo@PLT) was developed to relieve immunosuppression by achieving tumor vascular normalization. Endo@PLT reprogrammed the immunostimulatory phenotype, achieving excellent PD-1 immunotherapy in vivo.

From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues.

This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.

RK-270D and E, Oxindole Derivatives from Streptomyces sp. with Anti-Angiogenic Activity.

A chemical investigation of a culture extract from Streptomyces sp. RK85-270 led to the isolation and characterization of two new oxindoles, RK-270D (1) and E (2). The structures of 1 and 2 were determined by analyzing spectroscopic and spectrometric data from 1D and 2D NMR and High-resolution electrospray ionization mass spectrometry (HRESIMS) experiments. Compound 1 exhibited anti-angiogenic activities against human umbilical vein endothelial cells (HUVECs) without cytotoxicity. Results of Western blot analysis revealed that 1 inhibits VEGF-induced angiogenesis in the HUVECs via VEGFR2/ p38 MAPK-mediated pathway.

Trojan-Horse Diameter-Reducible Nanotheranostics for Macroscopic/Microscopic Imaging-Monitored Chemo-Antiangiogenic Therapy.

Although nanotheranostics have displayed striking potential toward precise nanomedicine, their targeting delivery and tumor penetration capacities are still impeded by several biological barriers. Besides, the current antitumor strategies mainly focus on killing tumor cells rather than antiangiogenesis. Enlightened by the fact that the smart transformable self-targeting nanotheranostics can enhance their targeting efficiency, tumor penetration, and cellular uptake, we herein report carrier-free Trojan-horse diameter-reducible metal-organic nanotheranostics by the coordination-driven supramolecular sequential co-assembly of the chemo-drug pemetrexed (PEM), transition-metal ions (FeIII), and antiangiogenesis pseudolaric acid B. Such nanotheranostics with both a high dual-drug payload efficiency and outstanding physiological stability are responsively decomposed into numerous ultra-small-diameter nanotheranostics under stimuli of the moderate acidic tumor microenvironment and then internalized into tumor cells through tumor-receptor-mediated self-targeting, synergistically enhancing tumor penetration and cellular uptake. Besides, such nanotheranostics enable visualization of self-targeting capacity under the macroscopic monitor of computed tomography/magnetic resonance imaging, thereby realizing efficient oncotherapy. Moreover, tumor microvessels are precisely monitored by optical coherence tomography angiography/laser speckle imaging during chemo-antiangiogenic therapy in vivo, visually verifying that such nanotheranostics possess an excellent antiangiogenic effect. Our work will provide a promising strategy for further tumor diagnosis and targeted therapy.