In 1971, Folkman proposed that tumours could not grow more than 2 mm³ without vascular supply because of insufficient oxygen and nutrition supply and poor clearance of metabolic waste, which would further cause hypoxia or acidosis (31). The physiological angiogenic process is maintained under the dynamically relative homeostasis, which is being referred to as “angiogenic switch” (32). Once this homeostasis is disrupted in tumours, the “angiogenic switch” will be active, and the vascular endothelial cells will be affected to upregulate the secretion of angiogenic promoters and downregulate the secretion of angiogenic inhibitors (33, 34). Over the past 50 years, the complex mechanisms of tumour angiogenesis have been exposed with more intensified researches.

Different types of angiogenic regulators could be released from tumour cells, blood, endothelial cells, and extracellular matrix (35, 36). Currently reported angiogenic promoters include vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming growth factor (TGF), fibroblast growth factor (FGF), angiopoietin-1 and -2 (ANG-1 and -2), and platelet-derived growth factor (PDGF), while angiogenic inhibitors include angiostatin; endostatin; platelet factor-4; tissue inhibitors of metalloproteinases (TIMPs); thrombospondin-1 (TSP-1); interferon (IFN)-α, -β, and -γ; and interleukin (IL)-12 (37). Some biological pathways like metabolic stress (hypoxia, hypoglycaemia, and lower pH), gene mutation (activation of oncogenes and inactivation of anti-oncogene), inflammatory response (tissue inflammatory infiltration), and mechanical stress (interactions by proliferating cells) can turn on the “angiogenic switch”, further resulting in tumourigenesis (38, 39). Among these pathways, hypoxia plays an important role in driving tumour angiogenesis, which can stimulate the expression of angiogenic stimulating factors in cancer cells. The transcriptional programs mediated by hypoxia-inducible factor (HIF) can activate hypoxia, which acts as a central regulator of detection and adaptive oxygen levels. HIF promotes the overexpression of VEGF A (VEGFA) and its receptors VEGF receptor-1 and -2 (VEGFR-1 and -2) (16). Moreover, HIF can promote the expression of ANG-2, which helps the proliferation of endothelial cells in hypoxic tumour areas, further destroying the integrity of the vascular wall (40). Tumour hypoxic conditions can also upregulate the expression of PDGF, which conducts as the mitogen of fibroblast and mesenchymal cells and induces different angiogenic actions (41). Additionally, matrix metalloproteinases (MMPs) can degrade the extracellular matrix, further mediating various changes in tumour microenvironment to advance the angiogenic process (42).

In the past 20 years, various anti-angiogenic agents were developed and prolonged the survival time of patients to some extent. Among them, more than 10 anti-angiogenic agents have been approved for the treatment of different digestive malignancies ( Table S1 of the Supplementary Material) (43, 44). The mechanism of such agents is to prevent tumour cells from obtaining nutrition by restricting available blood vessels and blocking the formation of novel blood vessels in tumour sites. Briefly, the mechanisms of most existing anti-angiogenic strategies include blocking the interactions of VEGF and VEGFR to their respective receptors ( Figure 1 ) (43). It was also reported that metronomic chemotherapy, which was defined as using small doses of the high-frequency chemotherapeutic drug to achieve a lower but effective range of drug concentrations over long periods without significant toxicity, could downregulate VEGF, further upregulating the expression of TSP-1 to play an important role in inhibiting tumour angiogenic dormancy (45–47)[a-c]. However, these therapies often have adverse reactions like drug resistance, toxicity, and even thrombotic and haemorrhagic diseases (48).

Despite that anti-angiogenic therapies sometimes stabilize diseases and prolong survival, such treatment might lead to more drug-resistant tumours and a higher patient recurrence rate. Such clinical harm might be related to the compensatory upregulation of angiogenic factors, further promoting tumour angiogenesis and tumour escape mechanism, which lead to acquired drug resistance. Among them, hypoxia plays an important role in tumour resistance to anti-angiogenic therapies and leads to more aggressive metastatic diseases with worse prognosis. Hypoxia-related HIF-1 pathway plays an important role in the resistance to anti-angiogenic therapies and is the main survival factor for cancer cells to overcome the hypoxic environment. Hypoxia is reported to regulate hepatocyte growth factor/mesenchymal–epithelial transition factor (HGF/c-MET) signal pathway, further activating mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) cascades, phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, and so on to promote tumourigenesis, progression, and drug resistance (49–52)[y3-y6]. In the phase III METEOR trial, advanced renal cell carcinoma (RCC) patients after previous VEGFR-targeted therapy were given cabozantinib (tyrosine kinase inhibitor), which could raise the survival rate (53)[y7].

For example, the anti-angiogenic efficacy of bevacizumab might be greatly weakened by the alternative pro-angiogenic signals generated during tumour proliferation and metastasis (46). The hypoxic microenvironment produced in the anti-angiogenic process could induce HIF-1 α and stimulate the expression of β1 integrin, which had been upregulated in bevacizumab-resistant tumours. Meanwhile, targeting β integrin could enhance anti-angiogenic therapies and inhibit the growth of bevacizumab-resistant tumours in xenograft models (54)[y8]. Additionally, many preclinical and phase I/II clinical trials have shown that a single anti-angiogenic strategy cannot effectively inhibit tumour growth, which promoted the development of multi-drug combination therapies (55). However, in addition to causing serious side effects, combination therapies usually performed poor biodistribution and pharmacokinetic characteristics (56).

With the development of science and technology, the field of nanobiology has attracted increasing attention in recent years. Nanotechnology-based medicine, also known as nanomedicine, has promoted tremendous advances in cancer treatment, especially in the areas of targeted drug delivery and medical imaging. Meanwhile, nanomedicine has made remarkable achievements in the research and development of drug development for clinical tumour treatment. Among them, many nanobased drugs have been used in the clinical chemotherapy of multiple gastrointestinal tumours, such as colorectal cancer, including doxorubicin liposomes, paclitaxel liposomes, and albumin-bound paclitaxel (27). The drugs mentioned above not only can improve the local treatment concentration but also can significantly reduce the non-specific toxicity of organs. Moreover, they can solve the problem of allergies to solvents (such as castor oil) caused by the poor water solubility of some common chemotherapy drugs (such as paclitaxel), further improving the quality of life of patients (57). These nanoparticles take different easily modified and highly biocompatible materials as their main body (such as organic compounds, proteins, lipids, and polymers), which are rationally modified and designed to be multifunctional drugs to achieve specific imaging and precise treatment of tumours (58).

Passive-targeting nanomaterials, which can be transported into tumour tissues through the EPR effect, are also the most widely studied nanoparticle drug delivery systems at present. To ensure that the tumour tissues receive sufficient nutrients and oxygen to facilitate rapid tumour growth, the blood vessels of most solid tumours have structural defects and produce a large number of vascular permeability factors so that most tumours exhibit high vascular permeability (63). The phenomenon produced by this special pathological anatomy that can promote the accumulation of nanomaterial substances in tumour tissues is called the EPR effect, which mainly manifests as macromolecules with molecular weights greater than 40 kDa selectively leaking out of tumour tissues and accumulating in solid tumours but not in normal tissues (64). The EPR effect is mainly related to the size of nanoparticles. Briefly, when the diameter is less than 4 nm, nanoparticles are not only likely to be filtered through the glomerulus in the systemic circulation and then discharged through the kidney but also diffuse back into the blood circulation after entering the tumour tissue because of the large pores between the vascular endothelium, which reduces the passive-targeting effect.

Nanoparticles greater than 400 nm in diameter are easily swallowed up by the reticuloendothelial system as foreign matter during blood circulation. Even if they reach the blood vessels near the tumour, they cannot permeate into tumour tissues because they are larger than the blood vessels. That is why the EPR effect is best when the size of the nanoparticles is from 20 to 200 nm (65–67). The EPR effect based on the characteristics of solid tumours is a milestone for tumour-targeted drug delivery and has been widely used in the development of nanobased antitumour drugs.

Stimulus-responsive nanoparticles achieve targeted delivery and controlled release of drugs by responding to the stimulation of physics, chemistry, and biomolecules (68). Their advantage is that they can realize the controlled release of drugs through the stimulation of trigger conditions, further reduce the loss of drugs during the process of blood circulation and reduce the toxicity of drugs (69).

It is well known that tumour tissue has a lower pH than normal tissue because cells in normal tissue are powered by oxidative phosphorylation, while in tumour tissue, cells are powered by glycolysis, resulting in the production of large amounts of lactic acid, which is known as the Warburg effect (70). The pH value in normal tissues is close to neutral (7.4), while in most tumour cells, it is slightly acidic (≤6.5) (70). Nanoparticles are prepared using pH-dependent chemical bonds to make them stable under physiological conditions. In a weakly acidic tumour environment, the chemical bonds can break, release the drugs, and improve the local accumulation rate of drugs in the tumour site (71).

According to the literature, cancer stromal cells actively secrete glutathione (GSH), resulting in a concentration of GSH in tumour cells (2~10 mmol/L) 100~1,000 times that in normal cells (2~20 μmol/L) and 100 times that in normal tissue, resulting in a strongly reducing environment in colorectal cancer (72, 73). Due to the existence of the mercaptan group in GSH, it can act as a reducing agent and become an important antioxidant, further decomposing some essential chemical bonds such as disulfide bonds and diselenide bonds (74, 75). Therefore, GSH stimulation-responsive nanoparticles are widely used for targeted delivery and controlled release of antitumour drugs. In addition, temperature, magnetic force, light, electric field, force, ATP, DNA, RNA, and enzymes can also be used as factors to stimulate drug release in nanoparticles, further improving the tumour treatment efficiency (76, 77).

Active-targeting nanomaterials, a novel approach to antitumour nanotechnology, can specifically bind to receptors overexpressed on the surface of tumours and tumour vascular endothelial cells by modifying the corresponding ligands on the surface of nanoparticles. Active targeting mainly depends on the interaction between ligand molecules and the surface receptors of tumour cells. Therefore, the ideal ligands used for active targeted delivery of antitumour drugs should be able to bind to tumour cells as much as possible but not to normal cells. A variety of ligands have been used for active antitumour drug targeted delivery, including folic acid, glucose, peptides, proteins, antibodies, and small interfering RNAs (siRNAs) (78, 79). The advantage of active targeting nanocarriers is that off-target effects can be avoided as much as possible (80). In summary, the aim of active targeting nanomedicine is to achieve a high affinity between receptors and ligands. Compared with passive targeting, the active targeted nanomaterial delivery system can enhance the binding of nanomaterials to tumour cells, reduce the non-specific uptake of nanomaterials, avoid the generation of drug resistance, and increase the distribution of drugs at the tumour site (81). In addition, nanocarriers have a variety of drug delivery capabilities, such as timely administration of chemotherapeutic drugs, targeted drugs, prodrugs, and drug kinases (82).

Because different tumour stages require corresponding treatment methods, the treatment of digestive tumours largely depends on accurate imaging diagnostic technology. CT, MRI, and PET are the most commonly used imaging techniques for diagnosing digestive tumours in the clinic. Nevertheless, these techniques are mainly based on the histomorphology and metabolic changes of tumours, which exhibit poor sensitivity in some cases, such as micrometastasis and small tumours (83). Nanoparticles can wrap high concentrations of imaging agents such as iodine, magnetic materials, and radioactive substances inside themselves to amplify the signals generated by tumours. In addition, nanocarriers can weaken the signal intensity of normal tissue, further reducing any interference with the diagnosis (84, 85).

In addition, new technologies such as near-infrared (NIR) fluorescence imaging can be used to observe the tissue morphology and metabolism, providing additional possibilities to detect important anatomical structures and tumour lymph node metastasis in real-time during surgery (86). The wavelength of NIR fluorescence is from 700 to 900 nm, with high tissue penetration (at the centimetre level) (87). After packaging NIR agents into nanoparticles and injection, the fluorescence signal can be captured by a laparoscopic fluorescent imaging system in real time, while human eyes are not sensitive to the NIR wavelength, and their presence will not change the surgical field.

Phototherapy, a light-mediated therapy, has gradually attracted increasing attention recently because of its advantages of minimal invasiveness, spatiotemporal controllability, and low toxicity in tumour treatment. Phototherapy includes photodynamic therapy (PDT) and photothermal therapy (PTT). PDT mainly relies on photosensitizers to absorb energy under light conditions, causing a series of photochemical and photobiological reactions and producing cytotoxic substances such as reactive oxygen species (ROS), which selectively damage tumour tissues (88). Indocyanine green (ICG), which has been approved by the Food and Drug Administration (FDA) for intraoperative fluorescence imaging in the clinic, is currently widely studied as a PDT agent due to its antitumour effects (89). The principle of PTT is that the photothermal medium converts light energy into heat energy after being irradiated by a laser, causing an increase in the local tissue temperature to achieve the killing effect (90). PTT has a wide antitumour spectrum because the process does not need oxygen. Additionally, most PTT agents are excited by NIR lasers, which can penetrate deeply into tissues and kill more tumour cells (91).

A synergistic system of phototherapy and chemotherapy was constructed through nanotechnology, in which the improvement of vascular permeability caused by phototherapy could increase the accumulation of nanoparticles in tumours, further enhancing the effect of chemotherapy (92). The thermal effect induced by PTT not only promotes the release of drugs by the nanoparticles but also changes the permeability of the cell membrane, further increasing the endocytosis of cancer cells to chemotherapeutic drugs (93). Nanotechnology can integrate different therapeutic functions into single nanoparticles, achieving a more thorough treatment mode and bringing new ideas and hope for tumour treatment. Moreover, nanoparticles can achieve tumour theranostics, which means that effective treatment is performed at the same time as tumour diagnosis, while the curative effect is monitored by diagnostic methods at the same time (94).

Metal nanoparticles have been widely considered with various applications in digestive tumours for anti-angiogenic treatment. Among them, gold (Au) nanoparticles are considered one of the most appropriate therapeutic options against tumours, and they have the advantages of chemical stability, small dimensions, low cytotoxicity, and inherent biocompatibility (100). Additionally, some studies have indicated that Au nanoparticles (AuNPs) possess anti-angiogenic properties. Mukherjee et al. first reported in 2005 that Au nanoparticles could specifically bind to VEGF-165 and basic FGF, further resulting in inhibition of endothelial and fibroblast cell proliferation in vitro as well as VEGF-induced permeability and angiogenesis in vivo. In addition, such nanoparticles exhibited no significant hepatic or renal toxicity in tumour-bearing mice (101). Based on the superior PTT characteristics of Au nanoparticles, CD44v6-GNSs (Au nanoparticle-conjugated CD44v6 monoclonal antibodies) were constructed. Such CD44v6-GNSs could inhibit the growth of gastric cancer and remarkably extend survival in tumour-bearing mice. Moreover, photoacoustic imaging indicated that CD44v6-GNSs could specifically target the gastric cancer vascular system after intravenous injection in vivo (102).

Furthermore, Au nanoparticles possess considerable advantages as carriers for targeted drug delivery. 5-Fluorouracil (5-FU), a thymidylate synthase inhibitor, is a commonly used chemotherapeutic drug against colorectal cancer with various side effects, such as bone marrow suppression, anorexia, and vomiting (103). Liszbinski et al. loaded 5-FU on Au nanoparticles coated with anti-EGFR (EGF receptor) antibodies to treat colorectal cancer. Such AuNP-5FU-EGFR nanoparticles showed superior efficiency in apoptosis induction over single 5-FU with no significant cytotoxic effects in human colorectal cancer cells (104). Delivering siRNA to tumour tissues has always been a great challenge. Because of their higher molecular weight and polyanionic properties, naked siRNAs would be degraded swiftly by serum ribonucleases, causing difficulties in crossing cellular membranes (105). It was reported that Au nanoparticles might be an appropriate and safe choice to deliver siRNA. A novel sequence of siRNA that targeted the oncogene c-Myc was designed and bound to branched polyethylenimine (bPEI)-modified Au nanoparticles. Such siRNA/bPEI/AuNPs could effectively deliver siRNA into human hepatoma cells and successfully silence the c-Myc gene with no significant cytotoxicity (106). Interestingly, the expression of the c-Myc gene was positively correlated with the expression of proangiogenic-related genes in many digestive tumours, including hepatocellular carcinoma, pancreatic cancer, and colorectal cancer (107–109).

Radiation therapy is a common clinical treatment for digestive tumours and could be used as a supplement to neoadjuvant therapy or as an auxiliary mean to prevent postoperative tumour recurrence. As a high atomic number element, Au could cause tumour tissue to have a mass energy coefficient and a higher atomic number than normal tissue while targeting the tumour region, further improving the treatment rate of radiotherapy. Au nanoparticles could enhance the efficacy of radiotherapy by regulating the cell cycle, inducing DNA damage, producing oxidative stress, and potentially interfering with bystander effects (110). Alhussan et al. functionalized Au nanoparticles with polyethylene glycol (PEG) and arginine-glycine-aspartate (RGD), the ligand for integrins, to acquire the GNP_PEG-RGD complex. GNP_PEG-RGD could not only target pancreatic cancer cells but also be used as a drug carrier and radiosensitizing agent. Moreover, the uptake of GNP_PEG-RGD by cancer-associated fibroblasts (CAFs) could be 10% higher than that of pancreatic cancer cells, causing the targeted killing of CAFs and achieving an antitumour effect (111). As a significant stromal cell component, CAFs could promote angiogenesis in digestive tumours by upregulating proangiogenic factors and controlling the biomechanical properties of the tumour matrix, such as elasticity, stiffness, and interstitial fluid pressure (112, 113). There are also studies reporting that biodegradable honeycomb-like gold nanoparticles (HGNs) could act as both radiosensitizing agents and photothermal agents to achieve synergistic photothermal radiotherapy. Such an approach could help nanoparticles accumulate more efficiently to improve the oxygen supply and damage double-stranded DNA in the tumour tissues of xenograft pancreatic cancer mice (114).

As a trace element, copper (Cu) plays an important role in multiple biological processes, such as oxidative metabolism, angiogenesis, tumourigenesis, metastasis, and relapse, while its imbalance can cause various diseases (115). A retrospective study demonstrated that a higher serum copper level was associated with relapse or disease progression in haematological malignancies. In addition, it was positively related to some adverse prognostic markers in chronic lymphocytic leukaemia, such as an increased percentage of unmutated IgVH and higher expression of ZAP70 and CD38 (116). Bai et al. reported hollow copper sulfide (CuS) nanoparticles encapsulating sorafenib and surface modified with anti-VEGFR antibodies. While CuS-SF@CMV nanoparticles kill hepatoma cells by CuS-mediated PTT, sorafenib and anti-VEGFR antibodies inhibit tumour angiogenesis through the PI3K/AKT and Ras/Raf/MEK/ERK pathways to achieve continuous inhibition against tumour metastasis (117). Cui et al. modified the surface of CuS with PEG and cyclic RGDfK peptide [c(RGDfK)] to acquire CuS-PEG-c(RGDfK) nanoparticles, which not only possessed the property of selective tumour uptake but also significantly killed hepatoma cells through thermal ablation (118). There are also studies reporting that cetuximab was modified on CuS to acquire active targeting of CuS nanoparticles (CuS-Ab NPs) with excellent PTT efficacy and superior biocompatibility in xenograft models (119).

Silver (Ag) nanoparticles are another important therapeutic noble metal widely used in medical applications. Gurunathan et al. first reported that Ag nanoparticles could have anti-angiogenic potential by inhibiting the VEGF-induced PI3K/Akt cell survival signal in bovine retinal endothelial cells (120). It was also reported that Ag nanoparticles could inhibit the process of angiogenesis by exhibiting dose-dependent cytotoxic effects on endothelial cells (121). Ag nanoparticles also had effective antitumour activities in lung cancer, melanoma, cervical cancer, breast cancer, and lymphoma cell lines (122–124). Given the lack of relevant research, additional animal experiments and preclinical studies are expected to validate the effectiveness of Ag nanoparticles in treating digestive tumours.

Superparamagnetic iron oxide nanoparticles (SPIONs) are widely used as targeted drug carriers with superior biocompatibility, good chemical stability, and low toxicity (125). Wang et al. loaded gambogic acid onto magnetic Fe₃O₄ nanoparticles (MNP-Fe₃O₄) called GA-MNP-Fe₃O₄, which inhibited the migration and proliferation of pancreatic cancer cells and downregulated the downstream target gene of angiogenesis, VEGF (126). It has also been reported that using hyaluronate (HA)- and trimethyl chitosan (TMC)-recoated SPIONs could significantly prevent the angiogenesis of colorectal cancer cells (127). Additionally, SPIONs modified with vasculature-specific binding peptides could potentially be used to observe the angiogenic status of gastric cancer in vivo (128).

With the advantages of a large relative surface area, adjustable pore size, higher drug loading efficiency, easy functionalization, and good biocompatibility, silica-based nanoparticles have been widely used as drug delivery systems in nanomedicine (129). In addition, silicate nanoparticles have been found to have potential anti-angiogenic effects against retinal neovascularization. Jo et al. demonstrated that intravitreal injection of silicate nanoparticles could effectively reduce anomalous retinal angiogenesis in retinopathy mice without direct toxicity. The specific mechanism might be that such nanoparticles could inhibit VEGF-related angiogenesis by suppressing VEGFR-2 phosphorylation and blocking the activation of ERK (130). Additionally, Setyawati et al. confirmed that silica nanoparticles could inhibit the proliferation, migration, invasion, and viability of endothelial cells, further restraining angiogenesis by triggering the production of intracellular ROS and activating the p53 gene-related pathway. This study also reported that compared with 40- and 100-nm nanoparticles, nanoparticles with a diameter of 60 nm exhibited the most effective inhibitory effect against angiogenesis (131). In another study, mesoporous silica nanoparticles (MSNs) were used to encapsulate evodiamine (EVO) and berberine (BBR) to acquire a delivery platform with temperature and pH responsiveness. This dual drug delivery platform exhibited excellent synergistic therapeutic effects against angiogenesis, cell migration, and invasion in hepatoma and colon cancer cells (132). Fluorescent silica nanoparticles marked by endoglin aptamers have been demonstrated to interfere with the TGF-β pathway by binding to tumour vascular endothelial cell membrane proteins, further inhibiting angiogenesis and reducing vascular density in xenograft hepatocellular carcinoma mice (133). Silica-based nanoparticles have also been reported to have anti-angiogenic potential in pancreatic and colorectal cancers (134–136).

Carbon is the second most abundant element in the body, and the application of carbon-based nanoparticles such as graphene, nanodiamonds, carbon nanotubes, and carbon nanodots in the antitumour, especially anti-angiogenic, field has been widely studied recently (137). Murugesan et al. reported first that carbon-based nanoparticles such as graphite, multiwalled carbon nanotubes, and fullerenes exhibited remarkable anti-angiogenic activity against both FGF- and VEGF-induced angiogeneses in a chick chorioallantoic membrane model (138). Lai et al. found that bovine serum albumin-capped graphene oxide (BSA-GO) could strongly bind to VEGF-A₁₆₅ and act as an effective angiogenesis inhibitor. Such nanoparticles could thereby block the interaction of VEGF-A₁₆₅ with the VEGF receptor and stop the downstream signalling pathway of angiogenesis in hepatoma cells (139).

Recently, Ding et al. developed PEI-modified single-walled carbon nanotubes (SWNTs) to deliver VEGF-targeted siRNA (siVEGF) for synergistic targeted treatment against angiogenesis. The observations in xenograft pancreatic adenocarcinoma mice indicated that such nanoparticles could significantly accumulate in tumour tissues and inhibit the growth and angiogenesis of the tumours. Moreover, low cytotoxicity, good biocompatibility, and negligible organ toxicity were observed in this study (140). However, the renal clearance, toxicology, and biocompatibility of carbon-based nanoparticles are still controversial and limit their further application. Some studies have suggested that they might penetrate the cell membranes of healthy tissue, resulting in harmful inflammatory and fibrotic responses and cell death (141, 142).

Synthetic and naturally derived polymeric nanoparticles have also received great attention in various biomedical fields, especially in drug delivery systems for cancer treatment and other diseases (143). As a naturally alkaline polysaccharide, chitosan has been widely used as a candidate material for drug carriers, taking advantage of its biodegradability, lower immunogenicity, better biocompatibility, and non-toxicity (144). Chitosan-based nanoparticles have been widely used in the treatment of digestive tumours, including anti-angiogenic therapies. Zhang et al. designed N-deoxycholic acid-glycol chitosan (DGC) as a carrier loaded with the commonly used chemotherapeutic agent docetaxel (DCT) and the angiogenic marker peptide for gastric cancer (GX1) to obtain multifunctional vascular targeting nanoparticles (GX1-DGC-DCT). GX1 could effectively promote the uptake of nanoparticles by cells, as observed by confocal laser scanning microscopy. After intravenous injection of GX1-DGC-DCT, tumour growth in xenograft gastric cancer models showed a tumour inhibition rate of 67.05% compared with the single DCT group (145). Some similar studies in gastric cancer reported that chitosan oligosaccharide (COS)-conjugated selenium (Se) and carboxymethyl chitosan (CMCS)-conjugated norcantharidin (NCTD) could remarkably enhance its antitumour efficacy through regulating the VEGF-related pathway to repress angiogenesis with non-toxic effects (146, 147). In addition, the delivery of siRNA by chitosan-based nanoparticles was also studied extensively. Nikkhoo et al. reported carboxymethyl dextran-conjugated TMC (TMC-CMD) nanoparticles loaded with signal transducer and activator of transcription 3 (STAT3)-specific siRNA and BV6, a well-known inhibitor of apoptosis (IAP) inhibitor. The results showed that such nanoparticles could reduce both in vitro and in vivo tumour growth and angiogenesis by decreasing the expression of related genes, including TGF, VEGF, and FGF, in colorectal cancer (148). Some similar studies reported that chitosan-based nanoparticles loaded with IL-6-specific siRNA and HIF-1α-specific siRNA could inhibit colorectal cancer progression and angiogenesis (149, 150). Epirubicin (EPI), as an anthracycline derivative, is a first-line chemotherapy drug against various digestive tumours (151). Nasr et al. loaded EPI in chitosan nanoparticles to treat hepatocellular carcinoma, and it exhibited lower cardiotoxicity and superior results in reducing angiogenesis, overcoming resistance, and enhancing the therapeutic efficacy (152). Chitosan-based nanoparticles have also been reported as potential candidates for anti-angiogenic treatment in other digestive tumours, such as cholangiocarcinoma and pancreatic cancer (153–156).

PEG, polylactic acid (PLA), and polycaprolactone (PCL) are FDA-approved commercially available biodegradable copolymers that are widely used to prepare nanoparticles for drug delivery (157). Apatinib (a selective VEGFR-2 inhibitor) and DCT (Taxotere) are widely used for combined treatment in digestive tumours, but their curative effects appear to be impaired due to the disadvantages of their poor pharmacometabolic characteristics (158). Yu et al. constructed PEG-PCL liposomes as a drug delivery system for apatinib and DCT. They could achieve locally higher drug concentrations and prolong the release time, further decreasing angiogenesis, promoting apoptosis, and inhibiting proliferation in xenograft colorectal cancer mice (159). Liu et al. prepared PEG-PLA micelles to coencapsulate paclitaxel (PTX) and itraconazole (ITA) to produce PTX-ITA micelles (PIM) nanoparticles. PIM showed excellent systemic pharmacokinetics and increased drug accumulation in the tumour site. Additionally, PIM normalized blood vessels and inhibited tumour growth in both a human orthotopic pancreatic cancer model and genetically engineered spontaneous pancreatic ductal adenocarcinoma mice (160). Liposomal nanodelivery systems have also been widely studied in various digestive tumours, such as hepatocellular carcinoma and gastric cancer (161–163).