Current status and recent progress of nanomaterials in transcatheter arterial chemoembolization therapy for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) remains one of the most common cancers worldwide. Transcatheter arterial chemoembolization has become a common treatment modality for some patients with unresectable advanced HCC. Since the introduction of nanomaterials in 1974, their use in various fields has evolved rapidly. In medical applications, nanomaterials can serve as carriers for the delivery of chemotherapeutic drugs to tumour tissues. Additionally, nanomaterials have potential for in vivo tumour imaging. This article covers the properties and uses of several kinds of nanomaterials, focusing on their use in transcatheter arterial chemoembolization for HCC treatment. This paper also discusses the limitations currently associated with the use of nanomaterials.

Key Words: Transcatheter arterial chemoembolization; Hepatocellular carcinoma; Nanomaterials; Drug delivery system; Chemotherapy

Core Tip: This article comprehensively discusses the potential of transcatheter arterial chemoembolization combined with various nanomaterials in the treatment of hepatocellular carcinoma. By summarizing the characteristics and applications of liposomes, micellar nanoparticles, hydrogels, metallic nanoparticles, and metal-organic frameworks, it highlights the enhanced therapeutic efficacy and precision offered by nanotechnology. The review also explores the advancements in imaging techniques and the challenges and limitations of integrating nanomaterials into clinical practice. Ultimately, the manuscript provides insights into the promising future of nanomaterial-based transcatheter arterial chemoembolization in hepatocellular carcinoma treatment, with potential for significant clinical impact.

INTRODUCTION

Hepatocellular carcinoma (HCC) remains one of the most common types of cancer globally, and it has a high mortality rate. The World Health Organization predicts that by 2023, more than a million people will have died from liver cancer[1]. For patients with HCC, both the extent of liver function impairment and the tumour stage should be considered when choosing a course of treatment. Large solitary HCC and multifocal lesions without vascular invasion or extrahepatic spread that are consistent with the Child-Pugh A and B classifications are classified as intermediate-stage HCCs according to the Barcelona Clinical Liver Cancer algorithm[2]. Transcatheter arterial chemoembolization (TACE) is a localized treatment that typically utilizes the Seldinger technique, involving percutaneous puncture of the femoral artery, followed by catheter insertion into the coeliac or common hepatic artery for angiographic assessment. Based on hepatic arterial digital subtraction angiography, the tumour’s location, size, number, and feeding arteries are identified. Subsequently, super-selective catheterization of the tumour’s feeding artery is performed to facilitate chemotherapy infusion and hepatic arterial chemoembolization. TACE therapy, is guided by imaging and is particularly suitable for unresectable intermediate- and late-stage HCCs[3], but it is also a common and effective transitional treatment for patients awaiting liver transplantation[4]. In contrast to the normal liver, the major source of blood supply in HCC is the hepatic artery. Therefore, cancer cells growth can be inhibited by selectively delivering anticancer treatment to the artery supplying the tumour[5]. In a meta-analysis of randomized trials evaluating the prognosis of unresectable HCC, arterial embolization improved two-year survival compared with that of the control group; therefore, some patients with unresectable HCC may benefit from TACE[6]. In another study including 322 patients with HCC who could not be treated with surgery and were instead treated with TACE, the patients had a median survival time of 21 months and had 1-, 2-, and 3-year survival rates of 66%, 46%, and 33%, respectively. Thus, it is reasonable to hypothesize that TACE is a feasible and effective treatment for patients with unresectable HCC[7].

However, nanomaterials, due to their nanoscale dimensions, can traverse the interendothelial gaps of the tumour vasculature, enabling passive or active targeting of tumours. These materials penetrate and remain within the tumour interstitial spaces, which distinguishes them from microsphere-based materials. Furthermore, owing to their larger surface area, certain nanoscale drug delivery systems (DDSs) can carry higher loads of chemotherapeutic agents, enabling precise tumour targeting[8]. This capability has the potential to reduce the local drug dosage required during TACE, while maintaining therapeutic efficacy and minimizing local side effects. Additionally, unlike microspheres, some nanomaterials can serve as contrast agents to evaluate the efficacy of TACE in HCC, addressing the challenge of visualization limitations associated with microspheres. TACE with drug-eluting microspheres is a relatively new treatment modality that involves the infusion of microspheres loaded with a variety of chemotherapeutic agents into an artery. The microspheres regulate the rate at which the chemotherapeutic agents are released into the cancerous tissue and block specific blood vessels[9]. The use of doxorubicin (DOX)-loaded beads in TACE resulted in an increased tumour response rate and decreased alpha-fetoprotein levels in a study involving 62 patients with unresectable HCC. These findings suggest that drug-loaded beads may be candidates for improving the therapeutic effect of TACE[10]. Nanomaterials are composed of nanoparticles, which are defined as three-dimensional materials with at least one dimension in the nanometre size range (0.1-100 nm). Nanotechnology is a multidisciplinary field, and nanomaterials are currently employed in a variety of applications. In the medical field, nanomaterials are frequently employed in the diagnosis and treatment of cancer[11,12].

DDSs are technologies or methods designed to control drug release, enhance targeting, and optimize therapeutic efficacy, and they are currently being used in clinical settings to treat cancer[13]. Upon entering blood vessels, nanomaterials are retained in the tumour tissue for an extended period, resulting in high penetration and a long retention time. This potentiates the ability of chemotherapeutic medications to kill tumour cells (Figure 1). When nanomaterials enter tumour cells, they adhere to and subsequently release chemotherapeutic medications into the nucleus (Figure 2). According to our research, nanoparticles enhance the therapeutic effect of TACE both before and after chemotherapy. Thus, the use of nanoparticles in TACE is a promising chemotherapeutic approach. The use of nanoparticles for TACE therapy and imaging in HCC patients are discussed in detail in this article. We provide compelling examples from recent research to support the importance of this approach while carefully examining potential limitations and opportunities for future development.

Figure 1 Schematic diagram of the construction of a liver cancer model using mice. Cancer cells are transferred to the body’s organs through the bloodstream. By injecting drug-loaded nanomaterials through the hepatic artery, the nanomaterials are targeted to the cancer cells and release the chemotherapeutic drugs. Chemotherapeutic drugs enter the vasculature with an enhanced permeability and retention effect.

Figure 2 Nanomaterials loaded with chemotherapeutic drugs use their targeting properties to enter into the tumour cells. They cleave and release the chemotherapeutic drugs to reach the nucleus, thus killing the tumour cells.

TYPES OF NANOMATERIALS

Since their introduction in 1974, nanomaterials have played an important role in the diagnosis and treatment of cancer[14]. This provides a promising approach for overcoming the limitations of TACE in the treatment of HCC. Nanomaterials function as carriers for drug delivery, allowing them to selectively target cancer cells while avoiding healthy liver cells. DDSs can increase the effectiveness and safety of chemotherapeutic medications by controlling the rate, timing, and location of drug release, thereby directing the drug specifically to malignancies. With continuous advances in nanotechnology, an increasing number of practitioners are utilizing nanotechnology for cancer treatment and diagnosis. Consequently, there is an increasingly urgent need to develop nanomaterial-based approaches for the treatment and diagnosis of HCC. Various types of nanomaterials, including liposomes, micelles, metal nanoparticles (MNPs), magnetic nanoparticles, and nanogels, have been employed in the diagnosis and treatment of cancer. Below is a summary for each of the nanomaterials mentioned above, along with pie charts that show the most frequently used nanoparticles (Figure 3).

Figure 3 Nanoparticles are of various types and this paper focuses on a number of common classes and depicts their internal structure. MOFs: Metal-organic frameworks; LNPs: Lipid nanoparticles; MNPs: Metal nanoparticles; PEG: Poly-ethylene-glycol; SPIONs: Superparamagnetic iron oxide nanoparticles.

Liposomes

The phospholipid bilayer structures known as liposomes were first proposed to exist in 1965. Lipid nanoparticles, which are now extensively used in clinical practice, have a relatively good safety profile and can be used as drug delivery carriers[15]. Liposomes, for example, have received approval from the United States Food and Drug Administration for their application in cancer treatment, primarily for the delivery of encapsulated chemotherapy agents[16]. As drug delivery vehicles, liposomes have the ability to encapsulate both hydrophilic and hydrophobic drugs. Pastorino et al[17] reported that the use of liposomes as a delivery system can increase the sensitivity of terminal or metastatic melanoma to adriamycin. A similar study conducted by Patel et al[18] used tariquidar, an inhibitor of drug efflux transporter pumps, in combination with paclitaxel. These medications were encapsulated in liposomes with a long circulation time to overcome multidrug resistance, which is a common limitation in the ability of chemotherapy drugs to eliminate tumours. Symon et al[19] reported that adriamycin can be delivered to the nucleus of cancer cells in metastatic breast cancer via stealth liposomes.

However, liposomes have several constraints when employed as carriers for drug delivery. One such limitation is the rapid release of chemotherapeutic medicines from liposomes into the bloodstream before the liposomes reach the tumour site. This occurs because the stability of liposomes in the blood is influenced by destructive factors in the serum, such as high-density lipoprotein, which is a significant factor in the breakdown of liposomes. Additionally, liposomes activate the complement system in the serum, resulting in the formation of a membrane attack complex that causes drug leakage through hydrophilic channels[20]. To overcome this limitation, liposomes that can remain in the circulation for an extended period in vivo have been developed, including liposomes that contain biocompatible polymers, such as poly-ethylene-glycol, to prolong their circulation time[21,22]. Ren et al[23] employed Arg-Gly-Asp-modified targeted liposomes, which notably increased the accumulation of liposomes in HRT-18 cells in vivo, while also exhibiting a favourable safety profile. In addition, liposomes can be used for diagnostic imaging by encapsulating substances such as fluorescent probes[24]. When employed for in vitro imaging, liposomes can be colabelled with radionuclides to enhance in vivo positron emission tomography/computed tomography (CT) imaging. This approach yields superior outcomes for both diagnosis and treatment[25,26].

Micelles

Micelles are nanocolloidal particles that are spherical in shape and characterized by hydrophobic cores and hydrophilic shells. The size of these particles typically ranges from 5 to 100 nm[27], and they are currently being employed as drug carriers in the clinic[28-30]. The cores can effectively encapsulate wide ranges of drugs, especially hydrophobic drugs[31]. By evaluating the permeability of drug-loaded polymer micelles in tumours, Cabral et al[32] found that while various sizes of micelles can penetrate highly permeable tumours, only 30 nm polymer micelles can penetrate pancreatic tumours, resulting in lower penetration. Therefore, it is reasonable to hypothesize that smaller nanomaterials achieve better tumour penetration. Like other nanomaterials, micellar drug carriers exhibit inherent instability. Micelles can be classified according to two types of stability: Thermodynamic stability and kinetic stability. A crucial parameter for the thermodynamic stability of micelles is the critical micelle concentration (CMC). A smaller CMC indicates greater stability, as the degree of cross-linking between polymer chain segments is greater than that between small molecules. Consequently, the CMC of polymer micelles is lower than that of surfactant micelles, resulting in greater stability[27]. When polymer micelles enter the body, their stability can also be affected by some factors in the bloodstream, such as proteins[33]. Yokoyama et al[34] achieved enhanced anticancer efficacy by encapsulating adriamycin into polymeric micelles, as demonstrated in an in vivo experiment conducted in C26 mice.

Nanogels

Nanogels, or hydrogel nanoparticles, are polymer particles of submicron size (10-200 nm) that are composed of hydrophilic or amphiphilic polymer chains interconnected in a cross-linked structure[35]. Stimulus-responsive nanogels, a type of nanogel that responds to external stimulation by altering its own physicochemical properties, have been used in an increasing number of applications in recent years. These nanogels can be designed to have a variety of characteristics, including pH-responsive, redox-responsive, light-responsive, and heat-responsive characteristics[36-38]. Stimuli-responsive nanogels play a crucial role in drug delivery, especially in cancer therapy, owing to their capacity to regulate drug release in response to external stimuli. By responding to environmental changes, these nanogels facilitate controlled drug release, thereby improving therapeutic efficacy[39].

MNPs

In a number of disciplines, including clinical treatment, MNPs, which are distinguished by their small size and exceptional reactivity, are currently being employed as research materials[40]. Lin et al[41] proposed that lanthanide-doped nanoparticles have a unique fluorescence effect that emits visible light when lanthanide-doped upconversion nanoparticles are irradiated with infrared light; this feature makes them useful for biomedical applications such as cancer therapy, fluorescence imaging, magnetic resonance imaging (MRI) and drug delivery. Lanthanide-doped upconversion nanoparticles were developed for fluorescence visualization in animals and have excellent biocompatibility[42]. Zinc oxide nanoparticles (ZnONPs) are MNPs that are frequently used because of their environmentally friendly properties. They are biocompatible, nontoxic and also biodegradable, which makes them environmentally friendly and capable of enhancing the bioactivity of pharmacophores[43]. Hassan et al[44] performed in vivo and in vitro investigations utilizing ZnONPs in an HCC mouse model. Their findings indicated that, in contrast to the control group administered only diethylnitrosamine, the treatment group receiving ZnONPs alongside diethylnitrosamine presented decreased levels of the HCC markers alpha-fetoprotein and α-l-fucosidase, suggesting that ZnONPs exert anticancer effects on HCC. Moreover, ZnONPs can increase the generation of reactive oxygen species and liberate zinc ions (Zn²⁺), potentially resulting in cell death[45]. This nanomaterial could also be used for bioimaging applications[46]. Zhang and Liu[47] synthesized a nanoparticle designated PDMAEMA-co-PMAA-capped ZnO quantum dots (ZnO QD@PMAA-co-PDMAEMA) via a sol-gel technique, enabling the bioimaging of COS-7 cells. Yuan et al[48] developed a water-dispersible ZnO-QD-chitosan-folic acid carrier that can be loaded with adriamycin (DOX), and experiments revealed that this nanocarrier could achieve a loading rate of up to 75% and that the release of the drug was controllable. An additional type of metallic nanomaterials, known as superparamagnetic iron oxide nanoparticles (SPIONs), along with magnetic and targeted nanomaterials, can be instrumental in the diagnosis and treatment of cancer. The diagnosis of a variety of malignancies is significantly improved by the distinctive magnetic properties of SPIONs. These nanoparticles are currently utilized as diagnostic agents in MRI and have been employed to image HCC via MRI, as they can be directed to a specific target site in HCC via a magnetic field; this aids in the diagnosis of HCC via MRI and also contributes to the treatment of HCC[49]. Numerous types of SPIONs are available commercially, among which ferumoxides (dextran-coated SPIONs) and ferucarbotran (carboxydextran-coated SPIONs) are the two clinically approved SPIONs for liver cancer imaging[50].

Metal-organic frameworks

Recently, metal-organic frameworks (MOFs), a type of porous material that is characterized by a periodic reticular structure composed of diverse metal ions and organic ligands and is formed via molecular self-assembly, have attracted substantial attention in a variety of fields[51]. MOFs are distinguished by their high porosity, customizable pore dimensions, large surface area, and unique hydrophobic and hydrophilic interior microenvironments. These characteristics enable MOFs to accommodate the physicochemical properties of drugs as well as the shape of the loaded molecules, thereby enhancing drug loading efficiency. The aforementioned characteristics enable MOFs to serve as carriers in DDSs. MOFs are capable of serving as carriers in DDSs for cancer therapy, including photothermal therapy (PTT), photodynamic therapy, radiotherapy, and chemotherapy, due to the aforementioned characteristics. Li et al[52] achieved DOX release under near-infrared (NIR) laser irradiation by wrapping a zeolitic imidazolate framework-8 crystalline MOF around the core of gold nanorods. This approach also resulted in high photothermal efficacy under irradiation with an 808 nm NIR laser, with therapeutic effects on cancer. To increase the efficacy of liver cancer treatment, Qin et al[53] synthesized Mn-Ti MOF nanosheets as microwave sensitizers for microwave therapy applications. The porous structure of this nanomaterial increases the frequency of particle collisions and increases the ambient temperature. Moreover, this nanomaterial is suitable for MRI due to the Mn component. MOFs can also exert detrimental effects on cancer cells by influencing the microenvironment of the tumour. Meng et al[54] created a fibroblast-activating protein-α-targeting peptide-modified MOF for the encapsulation of blebbistatin, a nanomaterial that modulates the tumour microenvironment in response to light. Similarly, a multifunctional therapeutic diagnostic platform was developed using PB@MIL-100(Fe)d-MOF nanoparticles. This platform is capable of enhancing T1 and T2 MRI and can incorporate chemotherapy and PTT agents to enhance the efficacy of cancer treatment[55]. In conclusion, MOFs, as nanomaterials, can achieve specific imaging characteristics when integrated with specific metallic substances, hence serving a diagnostic function. Therapeutic efficacy can be enhanced via modifications incorporating photothermal or targeted effects. Although MOFs demonstrate considerable potential in drug delivery and medical imaging, the release of metal ions during their degradation could lead to toxicity and inflammation. Consequently, it is essential to assess the toxicity of MOFs before their clinical application[56].

Comparison of nanomaterial

In conclusion, we summarize the advantages and limitations of the aforementioned nanomaterials, focusing on their drug loading capacity, targeting ability, biocompatibility, and imaging capabilities (Table 1). Various nanomaterials exhibit unique advantages and limitations. MOFs, with tuneable porous structures, demonstrate exceptionally high drug-loading capacities, while liposomes effectively encapsulate both hydrophilic and hydrophobic drugs. All of these nanomaterials can be functionalized to enhance targeting and improve drug delivery precision. In terms of biocompatibility, liposomes, micelles, and nanogels exhibit excellent biodegradability and reduced systemic toxicity, while MNPs and certain MOFs may pose long-term biocompatibility challenges, necessitating further surface modifications. MNPs and MOFs, however, possess intrinsic imaging capabilities, making them suitable for CT, MRI, or fluorescence imaging and enabling theranostic applications. Some nanomaterials, however, face stability challenges. For example, liposomes and micelles are sensitive to environmental influences, leading to premature drug release, while certain MOFs may degrade under physiological conditions. Therefore, selecting an appropriate nanomaterial for TACE therapy requires a comprehensive evaluation of its drug-loading capacity, targeting ability, biocompatibility, and imaging functionality to optimize therapeutic outcomes in HCC treatment.

Table 1 Comparison of different nanomaterials: Liposomes, micelles, metal nanoparticles, nanogels, and metal-organic frameworks.

Nanomaterial	Drug loading capacity	Targeting ability	Biocompatibility	Imaging capability
Liposomes	High, capable of encapsulating both hydrophilic and hydrophobic drugs	Can be enhanced by ligand modification for active targeting	Excellent, highly biodegradable	Low, requires fluorescent probes or MRI contrast agents
Micelles	Moderate, mainly for hydrophobic drug delivery	Surface modification can improve targeting ability	Good, often composed of biodegradable polymers	Low, requires fluorescent labelling or radioactive probes
Nanogels	High, capable of encapsulating macromolecular drugs	Functionalization can enhance targeting	Good, hydrogel structure improves biocompatibility	Low, requires incorporation of contrast agents
MNPs	Low, primarily used as drug carriers	Targeting can be enhanced by magnetic properties or surface modification	Generally low, requires surface functionalization for improved biocompatibility	High, applicable for CT, MRI, and photoacoustic imaging
MOFs	Extremely high, with tunable pore structures	Targeting can be enhanced by ligand functionalization	Dependent on composition; some MOFs have low biocompatibility	High, can serve as CT/MRI/fluorescence imaging probes

CT: Computed tomography; MRI: Magnetic resonance imaging; MOFs: Metal-organic frameworks; MNPs: Metal nanoparticles.

USE OF NANOMATERIALS FOR TACE

TACE is categorized as a local-regional therapy; however, its ability to deliver chemotherapeutic drugs is insufficient, which may lead to their dissemination into systemic circulation, resulting in harmful effects throughout the body. The administration of chemotherapeutic agents is facilitated by the properties of nanomaterials. Currently, TACE can be performed to deliver nanomaterials to tumour cells for targeted drug delivery[57]. The nanomaterials used for TACE should exhibit low toxicity, high-dose delivery of chemotherapeutic agents, and effective targeting. Additionally, nanoparticle-based approaches can utilize the enhanced permeability and retention (EPR) effect of solid tumours to achieve drug delivery into tumours through active targeting[58]. The EPR effect refers to the increased permeability and retention of nanomaterials in tumour tissues due to the unique structure of tumour blood vessels. Tumour blood vessels are typically leaky and irregular, allowing nanomaterials to accumulate in the tumour while being poorly drained due to incomplete lymphatic drainage. This effect enhances drug delivery to the tumour and reduces side effects on normal tissues.

Zhao et al[59] employed C16-GNNQQNYKD-OH-based nanofibers as a hydrogel and delivery system, facilitating the localized release of tretinoin for HCC therapy. This nanomaterial effectively inhibited in situ HCC development and resulted in a twofold increase in the median survival of mice post-injection. The temperature sensitivity of nanomaterials can be used to improve the effectiveness of chemotherapeutic drugs in TACE therapy. Qian et al[60] utilized an adriamycin-loaded p(N-isopropylacrylamide-co-butyl methacrylate) nanogel-iodohexanol dispersion as a temperature-sensitive drug carrier, demonstrating substantial inhibitory effects on rabbit VX2 liver tumours in the context of TACE therapy. Zhao et al[61] developed a magnetic drug carrier system that includes iron, barium ferrite (BaFe₁₂O₁₉), and carbon-coated iron nanocrystals. After injection into liver tumours via TACE, this agent not only embolized the blood vessels supplying the tumour and improved the effect of the loaded chemical drugs but also released heat energy to kill tumour cells, thereby increasing the survival rate of patients with advanced HCC. Additionally, the targeting of drug carriers can be enhanced. A team of researchers fabricated a carrier that was loaded with DOX and contained periodic mesoporous organosilica (PMO) with magnetite (Fe₃O₄) nanoparticles and Cy5.5 molecules (Fe₃O₄@PMO-Cy5.5) for use in a VX2 rabbit model. The carrier was then delivered to liver tumours via the hepatic artery in conjunction with lipiodol chemoembolization. The results showed that Fe₃O₄@PMO-Cy5.5 inhibited the growth of liver tumour cells[62]. Inspired by the unique support ability and defense capability of wood cell walls, Zheng et al[63] fabricated DOX-loaded pN-kraft lignin nanogels (DOX-pN-KL) using KL via an emulsion solvent evaporation method. In vitro release studies revealed that pN-KL exhibited high encapsulation efficiency (99.5%) and DOX loading capacity (23.71%). In an in vivo experiment, TACE treatment with DOX-pN-KL significantly suppressed tumour growth in VX2-tumour-bearing rabbits. Additionally, DOX-pN-KL showed excellent biocompatibility in animal studies, although its biological safety in clinical applications warrants further investigation[63].

Hao et al[64] utilized bovine serum albumin (BSA) nanoparticles as drug delivery carriers for tirapazamine (TPZ), a bioreductive agent that is activated in hypoxic environments and exerts potent cytotoxic effects on tumour cells. The study demonstrated that BSA_TPZ effectively induced occlusion of peripheral blood vessels within the tumour, and no tumour vasculature reperfusion occurred by day 9 post-TACE treatment. Moreover, BSA_TPZ inhibited the growth of the primary tumour and also exhibited a synergistic effect on metastatic tumours[64]. The TACE procedure can be monitored using imaging approaches such as ultrasound or MRI, and a variety of nanomaterials can be employed as carriers and for in vivo visualization. After TACE treatment, residual lipiodol at the tumour site may hinder accurate CT evaluation of remaining tumour lesions. To address this issue, Chen et al[65] developed Dp-PEG modified lutetium/gadolinium-co-doped nanoparticles for post-TACE therapeutic assessment. Lutetium (Lu³⁺) and gadolinium (Gd³⁺) possess superior X-ray attenuation properties compared to lipiodol, enabling lutetium/gadolinium-co-doped nanoparticles to maintain high density in virtual non-contrast CT imaging. In contrast, lipiodol is effectively removed during virtual non-contrast imaging, thus allowing for a more precise evaluation of residual HCC lesions after TACE[65]. Li et al[66] created a nanotherapeutic agent that is based on the encapsulation of DOX and NIR-responsive copper sulfide (DOX@BSA-CuS). DOX@BSA-CuS is capable of being delivered to the tumour site and can also inhibit tumour growth after exposure to infrared NIR laser light. Additionally, this nanomaterial can be visualized via MRI during TACE treatment. Liposomes are the most widely used materials in clinical practice because of their superior biocompatibility and minimal cytotoxicity. Furthermore, metallic nanomaterials can be employed as thermotherapeutic agents for cancer treatment due to their ability to convert NIR light into heat in the context of photodynamic therapy or PTT.

SPIONs can be employed as MRI contrast agents for diagnostic purposes as a result of their magnetic properties. TACE has been demonstrated to be effective in managing unresectable HCC in the intermediate to advanced stages. Despite the increasing use of microspheres in TACE surgery, their lack of X-ray visibility necessitates the incorporation of a contrast agent for sufficient visibility during the procedure. Lipiodol emulsion combined with chemotherapy has progressively established itself as a standard treatment in patients undergoing TACE[67]. Nonetheless, post lipiodol deposition CT images may be compromised by numerous artefacts, hindering the precise evaluation of TACE treatment efficacy[68]. The retention time in blood and tissues is also short. However, some nanomaterials can function independently as imaging agents[69]. Compared with other nanoparticles, MNPs demonstrate superior visibility during therapy, particularly due to the ability to visualize metals in diagnostic settings. Therefore, we employed this capability to create a visual embolization system that could be integrated with TACE. We then employed ultrasound or MRI to gain a more comprehensive understanding of tumour location and size, which could provide valuable information for subsequent decisions about treatment plans. Moreover, nanomaterials can be used in posttreatment imaging and assessments of treatment efficacy. SPIONs, which are magnetic nanoparticles, can be administered to the tumour site and visualized via MRI because of their magnetic targeting properties. Additionally, the biocompatibility and biodegradability of SPIONs can reduce their toxicity to the human body[49]. One team prepared multifunctional lipid micelles combining semiconductor polymer dots and photosensitizers; these micelles have excellent MRI and photoacoustic imaging contrast capabilities and therefore enhance the antitumour capabilities of photothermal and photodynamic therapy and provide both anatomical and morphological information about the tumour[70].

Wang et al[71] synthesized magnetic liquid MNP calcium alginate microspheres that were laden with Fe@EGaIn NPs (Fe@EGaIn/calcium alginate microspheres). These microspheres are distinguished by their exceptional biocompatibility, which enables them to be used as therapeutic diagnostic agents. They can achieve effective tumour suppression in tumour-bearing rabbits in combination with TACE treatment, and their CT/MRI dual-modal imaging capability was demonstrated[71]. The effectiveness of TACE for the treatment of HCC can also be monitored using nanomaterials, as the delivery of microspheres to block the hepatic arteries may result in the induction of an acidic environment and hypoxia. Park et al[72] exploited this property to create a pH-responsive drug-eluting nanocomposite that was employed for the MRI-based detection of sorafenib, which was administered via an artery to treat HCC. We have summarized the quantitative data from the experiments mentioned above (Table 2) to provide a clearer visualization of the advantages of combining nanomaterials with TACE.

Table 2 Quantitative data on nanomaterials in transcatheter arterial chemoembolization treatment for hepatocellular carcinoma.

Ref.	Nanomaterial	Drug	Drug loading	Drug release	Therapeutic effect
[60]	p(N-isopropyl-acrylamide-co-butyl methylacrylate) nanogel	DOX	NA	24 hours: 50-70 wt (pH = 6.8, pH 7.4), 97 wt (pH= 5.3)	The tumour growth rate of VX2 tumour by TACE therapy of IBi-D dispersions were only 91%
[61]	iron/barium ferrite/carbon-coated iron nanocrystal composites	EPI	Saturation value of the carrier system was approximately 25.5 mg/g	Accumulation of more than 20% of drugs on day 20	The group (EPI + materials + magnetic hyperthermia) showed a stronger antitumor effect
[62]	Fe3O4@PMO-Cy5.5	DOX	27.65%	48 hours: 16% (pH 7.4), 39% (pH 5.5)	1 mg/mL (nanoparticle concentration): Death of 74.1% of the HepG2 cells
[63]	pN-KL nanogels	DOX	23.71%	24.2% (pH = 5.0), 20.5% (pH = 6.8), 21.8% (pH = 7.4)	Completely suppressed after 14 days
[64]	BSA NPs	TPZ	NA	12.89% (1 hour), 55.96% (168 hours)	Significant reduction in tumour growth rate
[66]	BSA-CuS NPs	DOX	55.52%	Exposed to 808 nm NIR irradiation, approximately 5% and 25% of total DOX were released at 5 and 24 hours	DOX@BSA-CuS can be efficiently delivered to the HCC tumour site and the DOX drug can be efficiently deposited at tumour tissue
[71]	Fe@EGaIn NP	CA	DL: 2.61% ± 0.01%; EE: 87.19% ± 0.26%	NIR group: 44.99% (0.1 W), 55.88% (1 W)	Excellent therapeutic efficiency was achieved with a tumour growth-inhibiting value of 100% in tumour-bearing rabbits
[72]	pH-DENs	Sorafenib	73.3% ± 2.5%	96 hours: approximately 80% (pH = 6.5), approximately 50% (pH = 7.4)	The pH-DENs triggered sorafenib release in response to acidic extracellular conditions, increasing drug concentration in the culture medium and enhancing therapeutic efficiency against HCC cells
[76]	P@PND nanogels	PT	NA	40 hours: > 80% (pH = 6.5)	The volume ratio of the treated tumours at 14 days to the initial tumour were 07 (Pt-P@PND)
[77]	HmA NPs	DOX	41%	24 hours: > 40% (pH = 4.5 or 6.5), 28.6% (pH = 7.4); 14 days: 83.9% (pH = 4.5), 74% (pH = 6.5), 53.4% (pH = 7.4)	24 hours: Apoptotic HepG2 cells, 28.8%

DOX: Doxorubicin; EPI: Epirubicin; TPZ: Tirapazamine; CA: Calcium alginate; PT: Cisplatin; IBi-D: P(N-isopropylacrylamide-co-butyl methacrylate) nanogel-iodohexanol dispersion; TACE: Transcatheter arterial chemoembolization; PMO: periodic mesoporous organosilica; KL: Kraft lignin; NPs: Nanoparticles; BSA: Bovine serum albumin; CuS: Copper sulfide; HCC: Hepatocellular carcinoma; NIR: Near-infrared; DEN: Drug-eluting nanocomposite; PND: PNIPAM-DEAMEA; NA: Not available.

NANOMATERIALS IN IMPROVING TACE EFFICACY

The prominent role of nanomaterials in TACE efficacy enhancement is mainly reflected in their unique physicochemical properties and targeted delivery capabilities. Nanomaterial-loaded drug systems can significantly increase drug concentrations at tumour sites while reducing systemic toxicity, thus enhancing therapeutic efficacy and improving patient tolerance.

Targeted delivery: Enhancing drug concentration and reducing toxicity

Nanomaterials improve the efficacy of TACE through precise drug delivery capabilities. By surface modification and functionalization, nanoparticles can achieve active or passive targeting to tumour tissues. For example, passive targeting based on the enhanced EPR effect allows nanomaterials to accumulate at tumour sites, while antibody- or ligand-modified active targeting further enhances selectivity. This targeted delivery strategy effectively increases the concentration of anticancer drugs at the tumour site while significantly reducing drug exposure to normal tissues, thereby lowering systemic toxicity. For example, DOX, an anthracycline drug, is one of the most widely used chemotherapeutic agents. However, its clinical application is limited by cardiotoxicity and other adverse effects. A study found that encapsulating DOX in liposomes can reduce its toxicity to cardiomyocytes[73].

Multifunctional nanomaterials: Expanding TACE therapeutic modalities

The application of multifunctional nanomaterials offers additional possibilities for TACE in the treatment of HCC. These materials deliver traditional chemotherapeutic drugs and also enable combined therapies such as PTT or sonodynamic therapy, thereby enhancing therapeutic efficacy. For instance, gold nanoparticles, with their excellent photothermal conversion properties, can effectively ablate tumours while sensitizing them to chemotherapy[74,75]. Additionally, magnetic nanoparticles can be guided by external magnetic fields for precise delivery and used as imaging agents for real-time monitoring. These properties enable multifunctional nanomaterials to provide better therapeutic effects in TACE treatment.

Stimuli-responsive nanomaterials: Precision release and enhanced safety

Stimuli-responsive nanomaterials further enhance the precision and safety of TACE treatment. These nanomaterials can sense specific characteristics of the tumour microenvironment (such as low pH, hypoxia, or high hydrogen peroxide levels) to achieve targeted drug release, thereby minimizing toxicity to normal tissues. Shi et al[76] developed a temperature-sensitive nanogel composed of polyphosphates, poly(N-isopropylacrylamide-b-2-(diethylamino)ethyl meth-acrylate) block polymer (pNIPAM-DEAMEA, PND), and cisplatin. Upon temperature elevation, Pt-P@PND nanogels undergo a sol-gel transition, enhancing the efficacy of TACE treatment. During tumour cell proliferation, glucose is extensively consumed, leading to the production of lactate via anaerobic glycolysis. The lactate is then exported into the extracellular space, causing a reduction in the pH of the tumour microenvironment and establishing an acidic milieu. Based on the acidic tumour microenvironment, Shi et al[77] developed pH-sensitive nanoparticles assembled via poly-his6-boligostyrene and zinc coordination. DOX-loaded HmA NPs demonstrated enhanced therapeutic efficacy in TACE treatment within the acidic tumour microenvironment, exhibiting remarkable tumour suppression effects[77]. Moreover, some materials (e.g., polylactide-co-glycolide or liposomes) exhibit biodegradability, significantly reducing the risk of material residue after treatment. This feature improves treatment safety and also ensures better long-term health outcomes for patients.

LIMITATIONS OF THE APPLICATION OF NANOMATERIALS FOR TACE

The majority of nanomaterials used for TACE treatment are currently in the animal experimental stage, although they can offer unique advantages and show promise for use in clinical applications. Since chemotherapy infusion and chemoembolization are performed within the catheter, with the embolic dose adjusted based on tumour characteristics, it remains unclear whether there is a risk of insufficient delivery of chemotherapeutic agents, their potential diffusion into the systemic circulation, and the extent to which such diffusion occurs. The VX2 hormone-based rabbit model is an excellent animal model for investigating the effectiveness of TACE in treating HCC. Although numerous biocompatible and low-toxicity nanomaterial-based agents have been reported, their effectiveness and potential detrimental effects in humans must be investigated in the future.

CONCLUSION

Compared with conventional TACE therapy alone, approaches that integrate nanoparticles for the synergistic treatment of HCC present distinct advantages. Some nanocarriers facilitate the targeted delivery of chemotherapeutic agents to tumour tissues, whereas some nanomaterials enable visualization of the treatment process, allowing real-time observation and subsequent feedback during therapy. These advancements hold promise in overcoming the limitations of traditional TACE therapies, such as drug resistance, poor targeting, and limited treatment precision. However, several critical challenges remain to be addressed. First, the scalability and reproducibility of these nanomaterials must be thoroughly evaluated through large-scale clinical trials to validate their safety, efficacy, and long-term stability in human subjects. Although preclinical studies show significant benefits, the translation from animal models to human clinical settings remains a major hurdle. Furthermore, it is essential to assess the potential for nanoparticle-induced toxicity, especially the long-term impact on liver function and other organs. Additionally, future studies should investigate whether the therapeutic efficacy of specific nanomaterials can be optimized for particular subtypes of HCC or for patients with distinct genetic or molecular profiles. Personalized medicine approaches, where nanomaterials are tailored to the specific needs of individual patients, could help maximize therapeutic outcomes and reduce adverse effects. Moreover, the development of combination therapies integrating TACE with other emerging treatments, such as immunotherapy or gene therapy, could further enhance the clinical impact of nanomaterials. In conclusion, due to the current trend of accelerated development of nanomaterials, TACE has the potential to become more effective with fewer side effects in the future.