Yuan et al.

Journal of Nanobiotechnology (2023) 21:68 Journal of Nanobiotechnology

https://doi.org/10.1186/s12951-023-01820-7

REVIEW Open Access

Multifunctional nanoplatforms application

in the transcatheter chemoembolization
against hepatocellular carcinoma
Gang Yuan1,2†, Zhiyin Liu3†, Weiming Wang2,4†, Mengnan Liu2,5, Yanneng Xu1,2, Wei Hu1,2, Yao Fan6, Xun Zhang1,
Yong Liu4* and Guangyan Si1*

Abstract
Hepatocellular carcinoma (HCC) has the sixth-highest new incidence and fourth-highest mortality worldwide. Tran-
sarterial chemoembolization (TACE) is one of the primary treatment strategies for unresectable HCC. However, the
therapeutic effect is still unsatisfactory due to the insufficient distribution of antineoplastic drugs in tumor tissues and
the worsened post-embolization tumor microenvironment (TME, e.g., hypoxia and reduced pH). Recently, using nano-
materials as a drug delivery platform for TACE therapy of HCC has been a research hotspot. With the development of
nanotechnology, multifunctional nanoplatforms have been developed to embolize the tumor vasculature, creating
conditions for improving the distribution and bioavailability of drugs in tumor tissues. Currently, the researchers are
focusing on functionalizing nanomaterials to achieve high drug loading efficacy, thorough vascular embolization,
tumor targeting, controlled sustained release of drugs, and real-time imaging in the TACE process to facilitate precise
embolization and enable therapeutic procedures follow-up imaging of tumor lesions. Herein, we summarized the
recent advances and applications of functionalized nanomaterials based on TACE against HCC, believing that devel-
oping these functionalized nanoplatforms may be a promising approach for improving the TACE therapeutic effect of
HCC.
Keywords Nanoparticles, Multifunctional, Transarterial chemoembolization, Hepatocellular carcinoma

† 5
Gang Yuan, Zhiyin Liu and Weiming Wang have equal contributors and National Traditional Chinese Medicine Clinical Research Base
co-first authors and Department of Cardiovascular Medicine, The Affiliated Traditional
Chinese Medicine Hospital of Southwest Medical University, Luzhou,
*Correspondence: China
Yong Liu 6
Department of Anus and Intestine Surgery, Traditional Chinese Medicine
lyong74@163.com Hospital Affiliated to Southwest Medical University, Luzhou 646000, China
Guangyan Si
Siguangyan@swmu.edu.cn
1
Department of Intervention Radiology, Traditional Chinese Medicine
Hospital Affiliated to Southwest Medical University, Luzhou 646000, China
2
State Key Laboratory of Quality Research in Chinese Medicine, Macau
Institute for Applied Research in Medicine and Health, Macau University
of Science and Technology, Taipa, Macau SAR, China
3
Department of Neurology, The Affiliated Hospital of Southwest Medical
University, Luzhou 646000, China
4
Department of General Surgery (Vascular Surgery), The Affiliated
Hospital of Southwest Medical University, Luzhou 646000, China

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Yuan et al. Journal of Nanobiotechnology (2023) 21:68
Introduction
Liver cancer generally refers to primary liver cancer as
the sixth most common cancer and the fourth cause of
cancer-related death globally [1]. Hepatocellular car-
cinoma (HCC) accounts for approximately 90% of all
cases of primary liver cancer [2]. Ablation, surgical resec-
tion, or transplantation are radical treatments for HCC
patients at an early stage [3]. However, HCC is asympto-
matic in the early stage and is often ignored. Most HCC
patients are diagnosed at intermediate and advanced
stages, and hence more than 70% of HCC patients miss
the best time for radical treatments [4]. Intra-arterial
therapy approaches (e.g., transarterial embolization, TAE
or transarterial chemoembolization, TACE) are consid-
ered as prioritized treatment options for HCC patients at
an intermediate stage according to the Barcelona Clinic
Liver Cancer (BCLC) staging system [5, 6]. As a palliative
therapy, TACE plays a critical role in treating HCC as a
stand-alone or combination therapy in any stage of HCC
or as a neoadjuvant treatment before liver transplanta-
tion [7].
Although the liver has dual blood supply, 95–98% of
the blood supply of most malignant hepatic tumors is
provided by the hepatic artery, while more than 75% of
the blood supply of healthy hepatic parenchyma is pro-
vided by the portal vein, which is the theoretical basis
for TACE treatment of HCC [8, 9]. The basic principle
of TACE is to block the blood supply of solid tumors
through the hepatic arterial route and, simultaneously,
administrate chemotherapeutic drugs to achieve the
effects of localized embolization (ischemic effect) and
chemotherapy (cytotoxic chemotherapeutic effect) [10].
In general, conventional TACE (c-TACE) uses lipiodol-
based emulsion as an antineoplastic-drug carrier plus
an embolizing agent to embolize the tumor-supplying
artery, which enables local delivery of antineoplastic
drugs by intra-arterial approach and reduces systemic
side effects compared with systemic chemotherapy [11].
Nevertheless, the lack of effective drug carriers and the
inability to control drug delivery to the targeted tumor
tissues leads to insufficient drug distribution in tumors
and rapid drug release. Therefore, HCC patients who
have undergone c-TACE therapy may still suffer recur-
rence and some systemic adverse reactions like postem-
bolization syndrome, including abdominal pain, fever,
nausea, vomiting, diarrhea, et al. [12–14]. In addition, the
hypoxic tumor microenvironment (TME) after emboliza-
tion can induce the survival of viable tumor cell popula-
tion and tumor neoangiogenesis, which is closely related
to the progression and metastasis of solid tumors [15,
16].
Drug-eluting beads (DEBs), which were first com-
mercially available in 2004, were invited to improve the
Page 2 of 21
efficacy of TACE and reduce systemic side effects [17].
The application of DEB-TACE has achieved emboliza-
tion of tumor vasculature, drug delivery, and controlled
release of drugs, resulting in higher concentration of
drugs within the target tumor and lower systemic con-
centrations compared with c-TACE. Several clinical tri-
als compared the safety and efficacy of DEB-TACE with
c-TACE, indicating that DEB-TACE reduced the inci-
dence of specific toxicity associated with doxorubicin
(DOX) [18], relieved postembolization pain in patients
[19], and decreased the frequency of abdominal pain and
fever [20]. Nonetheless, unexpectedly, DEB-TACE carries
a higher risk of hepatic artery and biliary damage than
c-TACE [21, 22]. Moreover, although drug-eluting micro-
spheres have been developed for decades, the mechanism
of drug incorporation limits the drugs that may be used
[23]. Generally, microspheres use either an ion-exchange
method or a swelling process followed by the interaction
of the drug with ionized side chains (i.e., carboxylate or
sulfonate groups) to achieve drug loading [24, 25]. There-
fore, only positively charged drugs with low molecular
weight such as DOX, Idarubicin, and Irinotecan may
be incorporated [14]. Furthermore, although a range of
existing microspheres cover 30–900 μm in size [14], they
still cannot reach the arterial-capillary level, reducing
penetration and the total tumor volume exposed to drugs
[23]. An abundance of evidence has revealed that DEB-
TACE does not appear to show more efficacy advantage
over c-TACE therapy, except for improving patient toler-
ability and reducing systemic drug reactions [19, 26, 27].
Therefore, it is urgent to develop new chemoemboliza-
tion systems to improve the therapeutic effect of TACE
and reduce the side effects.
Recently, the application of nanomaterials in HCC
diagnosis and treatment has attracted extensive atten-
tion [28–30]. Nanomedicine has provided novel possi-
bilities to conquer current challenges in TACE therapy.
Due to the unique features of nanomaterials, such as
nanoscale carriers, high specific surface area, and spe-
cific physicochemical properties, they have excellent
application in drug delivery [31], specific targeting
[32], enhancement of pharmaceutical properties [33],
co-delivery of multiple drugs [34], and visualization
of sites of drug delivery by combination with imag-
ing modalities [35, 36]. Moreover, some nanomateri-
als themselves also possess therapeutic properties [37,
38]. Hence nanomaterials can provide bright prospect
for early diagnosis and precise treatment of cancer [39–
41]. Currently, nanoplatforms based on TACE therapy
have been widely developed to enhance the therapeutic
effect and the safety of treatment for HCC. The most
significant superiority of multifunctional nanoplat-
forms in the combination of TACE therapy against
Yuan et al. Journal of Nanobiotechnology (2023) 21:68
HCC is that they can not only improve the distribution
of chemotherapy drugs in local tumor tissue but also
avoid the severe side effects caused by systemic drug
administration. Compared with traditional methods,
functionalized nanoplatforms also have the advantages
of active targeting ability, specificity, synergy, and inte-
gration of diagnosis and treatment. In addition, several
functionalized nanoplatforms have been developed to
cope with the worsened post-embolization TME (e.g.,
hypoxia, reduced pH, angiogenesis), such as calcium
carbonate encapsulated alginate microspheres that can
neutralize the pH of the tumor [42], HIF-2α-targeted
interventional chemoembolization multifunctional
microspheres [43], Tirapazamine-loaded CalliSpheres
microspheres (CSMTPZs) that can enhance synergy
between TPZ and embolization against liver cancer
[44], and multifunctional embolic microspheres with
inhibitory effect on angiogenesis [35], which have
shown great potential in enhancing chemoemboliza-
tion. The preliminary results showed that these func-
tionalized nanoplatforms can be combined with TACE
to play a synergistic anti-cancer role, which shows a
great prospect in enhancing the efficacy of TACE and
improving the TME.
This review summarized the applications of mul-
tifunctional nanoplatforms in the TACE treatment
against HCC (Fig. 1) and the related limitations and
future development prospect based on the grow-
ing literature in recent years, aiming to facilitate the
upgraded development of functional nanoplatforms,
Fig. 1 Applications of multifunctional nanoplatforms in the TACE treatment against HCC. Nanoformulations perform functions such as
embolization, chemotherapy, photothermal therapy, imaging, drug delivery, and drug-controlled release. The figure has been created using
Biorender
Page 3 of 21
broaden the prospects and applications of TACE, and
benefit HCC therapy.
Rational design of multifunctional nanoplatforms
for TACE procedure
The development of nanomaterials provides new pos-
sibilities to overcome the current challenges in TACE
therapy for HCC, which is mainly attributed to the
unique characteristics of nanomaterials in drug deliv-
ery, specific targeting, enhancement of drug properties,
combined delivery of multiple drugs, and visualization of
drug delivery sites by combined imaging methods [37].
As shown in Fig. 1, combining a multifunctional nano-
platform and catheter embolization in the treatment of
HCC has demonstrated a powerful effect. Apart from the
most basic chemotherapy and embolization function, the
multifunctional nanoplatform can also realize the func-
tion of local hyperthermia and image follow-up. In addi-
tion, it acts as a carrier for drug delivery and can achieve
controlled release of drugs in response to physical or
chemical stimuli (such as pH, ultrasonic, or tempera-
ture changes) inside and outside the tumor. Therefore,
the combination of multifunctional nanoplatforms and
transcatheter embolization has apparent superiority in
improving the efficacy and safety of TACE therapy for
HCC and imaging follow-up after treatment. It is a prev-
alent strategy that various functional nanomaterials are
integrated into the composites, which, as a multifunc-
tional nanoplatform, can be applied in the TACE proce-
dure to improve the diagnosis and prognosis of HCC.
Yuan et al. Journal of Nanobiotechnology (2023) 21:68
Various nanoscale drug delivery systems have been
developed, including micelles, liposomes, polymeric
nanoparticles, mesoporous silica nanoparticles (MSNs),
etc. [45, 46]. Herein, we mainly focused on designing the
nanoplatforms based on material category for developing
ideal co-delivery nanotherapeutics (Table 1), character-
ized by reduced systemic side effects, prolonged circu-
lation, targeting delivery, on-demand release, reversed
resistance, tumor visualization, and synergistic treat-
ment. Obviously, the trials of these different categories
of nanomaterials in the treatment of HCC via the TACE
therapy provide strong support for the development of
new functional nanoplatforms.
Ideal nano-carrier designed for TACE should possess
high load capacity to chemotherapeutic drugs, selec-
tivity toward cancer cells, drug-controlled release, and
intra- and post-operative visualization in real-time. They
can improve the solubility and chemical stability of small
molecules of drugs. In addition, targeted antitumor drugs
can reduce drug resistance of tumors. Moreover, con-
trolled release of drug-loaded NPs can protect drugs
from rapid excretion and biodegradation, thus improving
the pharmacokinetic parameters of drugs in vivo, pro-
moting the enrichment of drugs in local tumor tissues,
and improving the anticancer-targeting ability of drugs.
Table 1 List of representative nanocarrier platforms for TACE therapy of HCC
Material category Examples of nanoplatform
Liposome PEGy-lated liposomal; nano flexible
liposomes; RLBNs
SPION SPIO;
USPIO; SPION@PDA
Metal oxide NPs ­ rO2;
Iron Oxide; Z
Fe3O4;
As2O3;
ATONP
Metal NPs Tantalum NPs; Gold nanospheres
HAP HAP;
poly-L-lysine-modified HAP nanoplex
Polymeric NPs PLGA
Polymer gel SELPs;
hydrogels
MSN mesoporous silica nanoparticles, PEG polyethylene glycol, RLBNs reversed lipidbased nanoparticles, SPION superparamagnetic iron oxide nanoparticles, MHT
magnetic hyperthermal, ATONP arsenic trioxide nanoparticle prodrug, PLGA polylactic-co-glycolic acid, HAP hydroxyapatite nanoparticles, SELPs silk-elastinlike protein
polymers
Page 4 of 21
Therefore, developing multifunctional nanocomposites
with high drug loading efficacy, targeted delivery, sus-
tained release, and imaging properties for TACE therapy
of HCC is becoming a hot research topic in recent years
[45, 46, 71, 72]. As shown in Table 2, apart from drug
delivery, different kinds of nano-formulations possess
diverse functions such as hyperthermia, embolization,
imaging, etc., which are conducive to synergistic diagno-
sis or monitoring, and treatment of HCC.
Strategies for diagnosis and TACE treatment of HCC
based on multifunctional nanomaterials
According to the current literature about the application
of nanomaterials in the diagnosis and TACE treatment
of HCC, several common strategies are summarized as
follows.
Visualization (imaging)
Recently, the use of the contrast agent effect of nanoma-
terials combined with chemoembolization in treating
HCC has become a hot topic. Although microspheres
are widely used in the TACE procedure [14], they must
be mixed with contrast agents (e.g., iodine contrast
medium) to achieve visualization during the therapeu-
tic process since the microspheres cannot be visualized
Applications Material advantage Refs.
Drug-carrier; embolic agent Decrease in systemic toxicity of free drug; [47–49]
improve delivery to tumor tissue; prolonging
drug circulation and delaying its release
MRI contrast; drug-carrier; Improve the detection of viable tumors; [50–54]
embolic agent; PTT improve drug loading capacity; reduce systemic
toxicity; sustained drug release;
synergistic enhancement of PTT and chemo-
therapy; prevent drug resistance
MRI contrast; drug-carrier; Improve the detection of viable tumors; [55–61]
embolic agent improve drug delivery and enhanced its antitu-
mor efficacy; sustained drug release; ferroptosis
amplify the antitumor efficacy
Drug-carrier; X-ray contrast; Real-time imaging; long-term non-invasive [62, 63]
embolic agents; PTT re-examination;
synergistic enhancement of PTT and TACE
therapy
Embolic agent; gene vector Combined gene therapy, embolic therapy, and [64, 65]
nanotherapy at the tumor site; prevent resist-
ance of chemotherapies
Drug-carrier; embolic agent Biodegradable; sustained drug release; stabi- [66, 67]
lized lipiodol emulsion
Liquid embolic agent; Enhanced embolization capacity; facilitate [23, 68–70]
X-ray contrast agent; permeation of tumor vasculature; pH response;
drug-carrier resist revascularization; imaging; prolong drug
retention
Yuan et al. Journal of Nanobiotechnology (2023) 21:68 Page 5 of 21

Table 2 Multifunctional nano-formulations used in TACE therapy of HCC

Nano-formulations Materials Applications Drugs Refs.

Gold nanospheres HAuNS, lipiodol Drug-carrier; PTT; embolic agent DOX [63]
Nano-clusters pMNCs, lipiodol Drug-carrier; embolic agent; MRI DOX [73]
Nanocomposites α-Fe2O3 nanocubes, PDA, and lipiodol Drug-carrier; PTT; embolic agent; MRI DOX [74]
UiO-66/Bi2S3 NPs Drug-carrier; PTT; embolic agent DOX [75]
BSA, CuS NPs Drug-carrier; PTT; embolic agent; MRI DOX [76]
Microspheres complex Carrageenan, inhexol and SPION Biocompatibility, Drug-carrier; embolic agent; imaging (MRI and X-ray) DOX [53]
Gelatin and F­ e3O4 NPs Drug-carrier; PTT; embolic agent; MRI ADR [60]
Alginate and USPIO NPs Biocompatibility; Drug-carrier; embolic agent; MRI AMO [52]
Calcium alginate and tantalum NPs Drug-carrier; embolic agent; X-ray imaging real-time DOX [62]
USPIO nanocluster and alginate Drug-carrier; embolic agent; MRI MEAN [77]
PDA, SPION Drug-carrier; PTT; embolic agent; MRI DOX [54]
Microbubble complex Albumin NPs and Lipiodol Drug-carrier; drug release triggered by ultrasound; real-time monitor- DOX [78]
ing
Hybrid composites PVA and iron oxide nanoshell Drug-carrier; embolic agent; MRI DOX [55]
HAuNS hollow gold nanoshells, pMNCs porous magnetic nano-clusters, PDA polydopamine, CuS copper sulfide, SPION superparamagnetic iron oxide nanoparticles,
USPIO ultrasmall superparamagnetic iron oxide, MEAN 6-methoxyethylamino numonafide, PVA poly vinyl alcohol, ADR Adriamycin, AMO amonafide

under the X-ray, which to some extent affects the accu-
racy of embolization and limits postoperative tracking
and evaluation. Therefore, developing a visualized embo-
lization system is highly important in interventional
therapy [62, 79, 80]. As shown in Table 3, we listed the
representative multifunctional nano-embolization sys-
tem for imaging in TACE or TAE therapy of HCC.
For the application of nanomaterials in ultrasound
imaging, NPs are usually integrated into microbub-
bles which are ultrasonic contrast agents. Nanoparticle-
and nanotechnology, ultrasound nanomedicine has been
regarded as a highly promising and valuable tumor-spe-
cific theragnostic methodology, which will pave a novel
and efficient way for combating cancer [84, 85].
Biodegradable and image-visible (e.g., CT or MRI)
microparticles synthesized by NPs that can be tracked
in vivo have been developed as a form of multifunc-
tional nanocomposite (Table 3). Introducing radiopaque
elements (e.g., I, Ag, Ba, Ta, etc.) into microspheres to
enable visualization of the microspheres under X-ray

Bead LUMI™ containing iodine [86], ­BaSO4-sodium

coated microbubbles are stable and echogenic, and they
can release the cargo of drug-containing NPs with an
ultrasound trigger [83]. Incorporating drug-loaded nano-
carrier microbubbles in TACE preparation can monitor
the delivery of drug to the tumor in real time and enhance
the therapeutic efficacy of TACE (Additional file 1: Fig.
S1) [78]. Based on the unique advantages of ultrasound
is theoretically feasible. Studies have shown that DC
alginate microspheres [87], tantalum NPs calcium algi-
nate microspheres (Ta@CaAlg) [62], and molybdenum
sulfide nanosheets encapsulated in sodium alginate
microcapsules (MSMC) [82] can realize X-ray visualiza-
tion under both DSA and CT, which can act as visualized

Table 3 List of nano-embolization system for imaging in TACE or TAE therapy of HCC
Imaging Embolism system Contrast agent Drugs Synergistic therapy Refs.

Ultrasonic imaging DOX-NPs-MB Microbubbles DOX Ultrasound and TACE therapy [78]
X-ray imaging(CT/DSA) Fe@EGaIn/CA Fe@EGaIn DOX PTT, PDT and TACE therapy [36]
BaSO4/ALG BaSO4 N/A TAE therapy [81]
Ta@CaAlg Tantalum NPs DOX TACE therapy [62]
MSMC MoS2 nanosheets N/A TAE and microwave ablation therapy [82]
MRI Fe@EGaIn/CA Fe@EGaIn NPs DOX PTT, PDT and TACE therapy [36]
SPION@PDA SPION DOX PTT and TACE therapy [54]
Fe3O4-MS Fe3O4 NPs ADM TACE, microwave ablation, and ferroptosis [60]
DOX-NPs-MB doxorubicin-loaded albumin nanoparticle-conjugated microbubble, Fe@EGaIn eutectic gallium-indium alloy nanodroplets containing iron nanoparticles,
Fe@EGaIn/CA calcium alginate microspheres loaded with Fe@EGaIn NPs, BaSO4/ALG barium alginate microspheres loaded with in situ synthesized B
­ aSO4 particles, Ta@
CaAlg calcium alginate microspheres loaded with tantalum NPs, MSMC MoS2 nanosheets encapsulated in sodium alginate microcapsules, SPION@PDA polydopamine
coated superparamagnetic iron oxide NPs, Fe3O4-MS homogenous gelatin microspheres co-loaded ­Fe3O4 NPs, ADM adriamycin
Yuan et al. Journal of Nanobiotechnology (2023) 21:68 Page 6 of 21

embolization systems for TACE treatment of HCC. This
is very beneficial for precise TACE treatment, as well as
CT follow-up of tumor lesions after therapy.
In addition, MR visualization microspheres are usually
prepared by adding MR contrast agents to the micro-
spheres, including paramagnetic lanthanides, such as
cerium, lanthanum, rubidium, praseodymium, gado-
linium [88, 89]. Clinically, gadolinium-based chelates are
the mainstay of contrast agents for MRI. Nevertheless,
Food and Drug Administration (FDA) has issued many
warnings about their potential retention in patients’ bod-
ies, raising safety concerns because their toxicity can
elicit severe side effects [90]. Fortunately, the nontoxic
and biodegradable natural NPs such as iron oxide nano-
particles (IONPs) are potentially attractive alternatives
[91]. Superparamagnetic iron oxide (SPIO) MR con-
trast agents such as ferumoxides and ferucarbotran are
composed of nano-sized iron oxide crystals coated with
dextran or carboxydextran, which are clinically used for
liver MRI [92]. As a potentially helpful theranostic agent,
a hybrid composite made up of SPIO nanoshells encap-
sulating the anticancer drug DOX and bound together
by polyvinyl alcohol (PVA) has been developed to treat
HCC with TACE approach [55, 93]. This treatment strat-
egy not only achieves the functions of chemotherapy and
embolization for tumors but also uses the MR response
of SPIO nanomaterials, which is conducive to post-
operative MRI follow-up of lesions. Recently, studies
reported that SPIO nanoclusters alginate microspheres
[52], temperature-sensitive lipoid-barium alginate micro-
spheres (Tsl-BA-MS) [94], alginate-USPIO microspheres
composed of calcium alginate-USPIO nanoclusters [79]
could be visualized under MRI. However, we must be
aware that these MR visualizing microspheres can only
be used for the follow-up of tumor lesions after TACE
and they cannot realize real-time visualization during
the TACE process. Therefore, there is a need to develop
embolic materials that can be visualized in real-time dur-
ing the operation to achieve more precise and controlled
intervention.
Targetability
Active targeting
The targetability of nanocarrier is crucial to improve
treatment efficacy and reduce side effects during TACE
treatment for HCC. Drug-loaded NPs (nanomedicines)
can be delivered into tumor tissues through active or pas-
sive targeting. Active targeting is mainly based on spe-
cific expression of receptors or proteins on tumor target
cells. Nanocarriers are designed to precisely recognize
these receptors or proteins ligands through “receptor-
ligand” binding mode to achieve the purpose of active
targeting. Due to the active targeting properties of nano-
carriers, some specific ligands expressed on tumor sur-
faces, including peptides [57], proteins [95], antibodies
[96], and oligonucleotides [64], can become targets of
the nanocarrier delivery systems for cancer treatment
(Fig. 2).

Fig. 2 Application examples of active targeting strategy based on nanocarriers in TACE treatment of HCC. ① iRGD-modified nano-formulation
target integrin improves the tissue distribution of the drug and its antitumor efficacy [57]. ② Delivery of miR-375 by hollow NPs inhibits
P-glycoprotein (P-gp) expression and overcomes multiple drug resistance in HCC [95]. ③ Hyaluronic acid (HA)-based nanocarriers improve the
cellular internalization of chemotherapeutics and anticancer activities via targeting CD44 receptor-mediated endocytosis [96]. ④ Hydroxyapatite
NPs (nHAP) serve as gene vectors to elevate and synergize the therapeutic efficacy of TAE and target gene therapy [64]. ⑤ Application of
TACE combined with targeted NPs delivery of sorafenib (SFB-NPs) system recognizes and antagonizes VEGF specifically in treating HCC with
microvascular invasion [97]. The figure has been created using Biorender
Yuan et al. Journal of Nanobiotechnology (2023) 21:68
Integrins
The recurrence and metastasis of HCC after TACE ther-
apy remain the leading cause of poor prognosis of HCC.
Tumor metastasis is a complex process involving multi-
ple factors, among which the integrin-mediated adhe-
sion of tumor cells to the basement membrane is one of
the critical factors leading to tumor cell infiltration and
metastasis [98]. Integrins are receptor molecules on the
cell surface that mediate the adhesion between cells or
cells and extracellular matrix (ECM) [99]. Therefore, inte-
grins can be used as therapeutic targets to prevent liver
cancer recurrence and metastasis. Studies showed that
transarterial administration of GRGDSP (Gly-Arg-Gly-
Asp-Ser-Pro, integrin-inhibitor) loaded nanocarriers
combined with TACE significantly delayed tumor growth
and intrahepatic metastases compared with TACE alone
or TACE plus GRGDSP in an animal model of HCC [98,
100]. Another study evaluated the effect of transarte-
rial infusion of iRGD-modified and doxorubicin-loaded
zirconia-composite nanoparticles (R-DZCNs, which can
selectively recognize and bind to integrin) with lipiodol
on improving the distribution of DOX in liver tumors and
its antitumor efficacy. The results suggested that tran-
sarterial infusion of R-DZCNs with lipiodol improved the
distribution of DOX and enhanced its antitumor efficacy
[57]. The successful application of these strategies in ani-
mal experiments provides new reference for reducing the
recurrence and metastasis after interventional emboliza-
tion therapy of HCC.
P‑glycoprotein
Drug resistance, which is regulated by P-glycoprotein
(P-gp), is a critical obstacle to cancer treatment [101].
P-gp is located on cell membrane and is a typical molec-
ular pump that protects cells from invading harmful
foreign molecules. It can shield or pump harmful com-
ponents, such as chemotherapy drugs, out of the cell,
resulting in drug resistance. P-gp constantly searches
for foreign hydrophobic molecules and is described as a
“security guard” protecting cell safety. Therefore, P-gp is
an essential target for treating tumor drug resistance.
Studies have shown that miR-375 can inhibit the
expression of P-gp by inhibiting the expression of
hepatoma astrocyte up-regulated gene-1 (AEG-1) and
induce apoptosis in hepatoma cells [102]. Based on this
finding, researchers designed an experiment on lipid-
encapsulated hollow mesoporous silica NPs (HMSN)
carrying miR-375 and DOX (LHD/miR-375) in the treat-
ment of multidrug resistance in HCC [95]. The results
showed that LHD/miR-375 overcame drug efflux and
imported miR-375 and DOX into multidrug-resistant
hepatoma cells or tumor tissues, and that miR-375 car-
ried by LHD/miR-375 inhibited the expression of P-gp
Page 7 of 21
in HCC cells after it was ingested through phagocytosis
and endocytosis mediated by reticular and fossa proteins
and then released from the advanced endosome (Addi-
tional file 1: Fig. S2). The synergistic effect of miR-375
and HMSN significantly increased the uptake of DOX by
HCC cells and inhibited the growth of HCC cells. In addi-
tion, studies also showed that miR-375 and DOX played a
synergistic antitumor effect by promoting apoptosis [95].
Therefore, the combination of a nano-drug delivery sys-
tem and P-gp inhibitor may have potential application
value for MDR treatment of HCC. On this basis, devel-
oping a drug-delivery nanoplatform for TACE therapy of
HCC may have further clinical application value.
CD44
CD44 is a multifunctional transmembrane glycoprotein
overexpressed in numerous cancer cells’ cell membrane.
It is also a receptor of hyaluronic acid (HA), mainly
involved in cell proliferation, migration, and angiogen-
esis, and plays an essential role in cancer metastasis
process [103, 104]. HA is a naturally occurring polysac-
charide that is biocompatible, biodegradable, and non-
antigenic, and is widely used in biomedical applications
as a conjugate, hydrogel, nanogel, and many other roles
[105]. Recently, HA has been developed into nanoplat-
forms that recognize and bind CD44 for cancer therapy
[103, 104, 106].
There is increasing evidence proving that HA-based
nanocarrier systems targeting CD44 receptors play a
positive role in TACE therapy for HCC. Lee et al. devel-
oped DOX-loaded, hyaluronic acid-ceramide (HACE)
nanoassembly-releasing PLGA microspheres for TACE
therapy of liver cancer [96]. The result suggested that
these microspheres accelerated cellular accumulation
of DOX and enhanced its anticancer activities. In addi-
tion, HA-based nano-sized drug carrier-containing
Gellan gum microspheres were also developed as a mul-
tifunctional embolic agent for TACE therapy [107]. The
microspheres can effectively improve the stability of anti-
carcinogen, increasing drug-targeted affinity towards
cancer cells and drug availability. Undoubtedly, the appli-
cation of CD44 as a target, based on the HA-nano drug
delivery system in treating HCC by TACE, has become a
new therapy model, which will provide new therapeutic
strategies for targeted therapy of medium and advanced
HCC.
Gene target
Gene therapy has become a promising new treatment
strategy for unresectable HCC as hepatocellular car-
cinogenesis correlates with the activation of oncogenes
and dysfunction of anti-oncogenes [108]. Designing a
safe and effective transfection vector is the key to gene
Yuan et al. Journal of Nanobiotechnology (2023) 21:68
therapy. Although viral vectors are currently considered
to be most effective, safety concerns have limited their
clinical application, making non-viral vectors the focus of
attention of clinicians and researchers [109, 110].
Hydroxyapatite nanoparticles (nHAP) as a gene vector
transarterial embolization (TAE) can block tumor blood
supply and deliver the agents to the tumor area; higher
concentrations of drugs in tumor tissue can enhance
tumor cells’ specific gene uptake, making efficient, locally
targeted gene therapy possible [64]. Li et al. have found
that nHAP exhibit good liver cell compatibility, safety,
and tumor-specific inhibition [111]. Besides, with fea-
tures of a large surface and high surface energy, nano-
sized nHAP can absorb DNA and form a nano polyplex
[112]. A previous study explored the combined effect of
p53 and Rb in local TAE gene therapy in a rabbit VX2
model of HCC. The result showed that Rb worked syn-
ergistically with p53 in combined therapy mediated by
a poly-L-lysine-modified nHAP nano polyplex to aug-
ment the antitumoral effect through the downregulated
expression of essential genes related to apoptosis, necro-
sis, growth, differentiation, and multidrug resistance of
tumor cells [65]. Another study also explored the syn-
ergism of wt-p53 and synthetic material (such as poly-
lysine modified nHAP) in local nano-TAE gene therapy
of hepatoma [113]. These studies created a new gene
delivery route using nHAP, which promoted the applica-
tion of TAE-target gene therapy in HCC.
VEGF
Tumor tissue hypoxia induced by TAE will lead to the
expression of vascular endothelial growth factor (VEGF),
thereby accelerating the formation of new blood vessels,
which creates favorable conditions for tumor recurrence
and metastasis and is, therefore, one of the critical fac-
tors affecting the efficacy of TACE for HCC [114, 115].
Sorafenib and other anti-angiogenic targeted drugs are
based on these therapeutic targets. However, in clinical
practice, oral anti-angiogenic targeted drugs may cause
many adverse events such as decreased appetite, nau-
sea, vomiting, diarrhea, fatigue, hand-foot skin reaction,
hypertension, and weight loss, leading many patients
to discontinue or reduce the dose, and the rebound of
disease after discontinuation will lead to more serious
consequences [116]. In this regard, nano-drug delivery
systems have shown remarkable therapeutic advantages.
For example, an in vitro study reported that biodegrada-
ble polylactic acid drug-eluting microspheres loaded with
sorafenib and cisplatin had been prepared to achieve the
triple therapeutic efficacy of embolization, anti-angio-
genesis, and chemotherapy [117]. In addition, in some
studies, sorafenib and ferric oxide NPs were co-encap-
sulated in poly-lactide-glycolide (PLG) microspheres,
Page 8 of 21
which could not only realize the angiogenesis inhibi-
tion of sorafenib but also could be used for postopera-
tive MRI detection [35, 118]. Recently, preclinical, and
clinical studies also validated the therapeutic efficacy of
delivering sorafenib-eluting microspheres or nanocar-
rier systems used in combination with TACE for treating
HCC with microvascular invasion [56, 97]. These thera-
peutic strategies undoubtedly provide new ideas for solv-
ing angiogenesis and preventing tumor recurrence after
TACE therapy.
Passive targeting
Unlike the above active targeting strategies, passive tar-
geting serves as a basis for developing macromolecu-
lar anticancer therapy. The enhanced permeability and
retention (EPR) effect plays a vital role in passive target-
ing, which mainly relies on the anatomical and patho-
physiological characteristics of solid tumors and their
microenvironments, such as high vascular density in
tumor tissue based on angiogenesis, intermittent tumor
vasculature with leaky effects and poor drainage of tumor
lymphatic system [119, 120]. As shown in Fig. 3A, due
to the EPR effect, nanoformulations in circulation can
enter tumor tissues through the gaps between endothe-
lial cells in tumor blood vessels [121]. This effect further
enhances the preferential accumulation of nanocarriers
within tumor tissues and accelerates intracellular deliv-
ery including endocytosis, lysosomal fusion, escape,
cytoplasmic release, and combining the target organelle
(Fig. 3B) [46, 119, 122]. These properties of tumors pro-
vide favorable conditions for designing tumor-targeted
antitumor NPs. Drug-carrying NPs can increase the
accumulation of chemotherapy drugs in tumor tissues
through EPR effect, improve therapeutic effects and
reduce toxic and side effects by reducing unnecessary
release in normal tissues [123, 124]. This unique passive
targeting effect of nanomaterials on tumor tissue is highly
beneficial for developing multifunctional nanoplatforms
for TACE therapy of HCC, as it synergically enhances the
safety of the transarterial administration and promotes
more efficient drug absorption by the tumor.
Drug delivery
Facilitate drug delivery capacity
Nanocarriers can facilitate drug delivery mainly by
enhancing drug loading efficiency and intracellular
uptake. Surface modification of nanomaterials is a com-
mon functionalization strategy through which nanoma-
terials are functionalized with organic molecules such
as polymers [125], peptides [126], or cell membrane
coated-biomimetic NPs [127] on the surfaces of these
materials to facilitate drug delivery capacity in can-
cer theranostics. For example, to increase drug loading
Yuan et al. Journal of Nanobiotechnology (2023) 21:68
Fig. 3 Nanocarriers can facilitate the delivery of chemotherapeutics. A Nanoformulations accumulation in the tumor tissue relies on the enhanced
permeation and retention (EPR) effect. B Intracellular delivery of nanoformulations, including endocytosis, lysosomal transport, nanoparticle
degradation, and drug release. The figure has been created using Biorender
content, adding charged functional groups (polymeric
additives: polyallylamine hydrochloride, PAH, giving
them a positive charge, and polyacrylic acid, PAA, giving
them a negative charge) on the surface of calcium phos-
phate NPs to endow them with a corresponding charge
so that the target drug with the opposite charge can be
loaded through efficient adsorption [128]. In terms of
increasing the intracellular uptake of anticancer drugs,
peptides with a particular function, like cell-penetrat-
ing peptides (CPPs), have recently emerged as efficient
molecular transporters for intracellular drug delivery to
conquer biological barriers and deliver cell-impermeable
cargoes into cells [126]. The conjugation of CPPs to poly-
meric nanoplatforms enhances drug delivery efficiency,
thus increasing their therapeutic efficacy. In addition,
another nanoplatform, namely cell membrane coated-
biomimetic NPs, can overcome biological barriers by
escaping from immune clearance, opsonizing, and nego-
tiating with the vascular system [127, 129, 130]. All these
nanoplatforms have outstanding contributions towards
facilitating anticancer drug delivery and are expected to
play a positive role in TACE therapy of HCC.
Controlled drug sustained release
A critical factor limiting the therapeutic effect of c-TACE
is the instability of chemotherapeutic agents in the lipi-
odol-TACE system. DOX, cisplatin, and 5-fluorouracil
are the most commonly used chemotherapeutics for the
treatment of HCC; among them, tried for TACE therapy,
DOX-based chemotherapeutic agents appear to offer the
highest efficacy, but with response rates of only (20 − 30)
% and a minimal impact upon survival [131]. The main
reason is that the dispersion of hydrophilic drugs in the
hydrophobic lipiodol phase is not stable, and the drugs
Page 9 of 21
often separate from the emulsion, leading to an initial
burst drug release [67]. The rapid release of chemothera-
peutic drugs within a short period reduces the therapeu-
tic effects and increases the risk of systemic side effects
[132, 133].
Controlled delivery systems, which are used to load
chemotherapeutic agents and provide sustained release,
will address these limitations of the lipiodol-TACE sys-
tem and, hopefully, increase patient comfort and com-
pliance [134]. A more precise dose of chemotherapy can
be delivered to the tumor tissue as the chemotherapeutic
agents loaded into the drug-delivery carriers can be con-
trolled. The exploration of stimulus-responsive nanocar-
riers has been devoted to great efforts recently. As shown
in Fig. 4, controlled delivery nanocarriers are accom-
panied by triggered drug release in response to either
extracellular stimuli (pH, photothermal, enzymes) or
intracellular stimuli (pH, reduction, and enzymes) [45].
In addition, some external stimuli such as heat, light,
ultrasound, and magnetic fields also initiate the primary
release of nanocarriers. Among many stimuli, pH sensi-
tivity is most exploited to trigger drug release [135].
In general, the TME is weakly acidic (pH 6.8 − 7.2),
with a pH of 5 − 6 in the endosomes and a pH of 4.5 − 5.5
in the lysosomes [136]. Such an acidic pH gradient guar-
antees the pH-responsive release of drugs loaded on
nanocarriers. Liu et al. developed a pH-responsible mag-
netic DOX-loaded nano-system mixed with lipiodol for
MRI-guided photothermal-chemoembolization treat-
ment in an orthotopic liver tumor model [74]. This nano-
system exhibited unambiguous pH-triggered drug release
properties at acid TME because of the introduction of
the pH-sensitive dopamine (PDA). Such pH-dependent
control release behavior can be attributed to promoting
Yuan et al. Journal of Nanobiotechnology (2023) 21:68 Page 10 of 21

Fig. 4 Nanocarriers penetrate from blood circulation (I) into the tumor nucleus (IV) and are responsive to different stimuli. (I − II) Drug delivery
systems based on nanocarriers can enhance drug penetration and retention into the tumor tissues via the endothelial gap. Externally stimuli (e.g.,
heat, light, ultrasound, magnetic fields, etc.) or extracellular stimuli (e.g., acidic TME, thermal radiation, enzymes, etc.) can cause the nanocarriers
to release their cargos in the vicinity of the target tissue. (III − IV) Intracellular nanocarriers escape from the endosomes and release their drugs in
response to internal stimuli (e.g., pH, reduction, enzyme, etc.) and specifically bind to the target to exert anticancer effects. The figure has been
created using Biorender

protonation of hydroxyl in PDA molecules with reduced
pH value, which weakens the electrostatic bond between
PDA and DOX molecules [74]. Another research
reported that a multifunctional nano-system (UiO-66/
Bi2S3@DOX) could simultaneously achieve photother-
mal effects and low pH-triggered DOX release. In this
study, DOX release behavior was regulated by both pH
and NIR laser, which benefited the combined chemical
and photothermal therapy. The nano-system exhibited a
pH-responsive release behavior and an excellent photo-
thermal effect in a series of in vitro and in vivo studies
[75]. In addition, Lym et al. developed a novel sulfameth-
azine-based anionic pH-sensitive block copolymer (PCL-
PEG-SM) as an alternative approach for TACE [69]. The
copolymer underwent a sol-to-gel phase transition upon
altering the environmental pH. The release of DOX from
DOX-loaded copolymer hydrogels could be sustained
for more than four weeks in vitro, and the released DOX
retained its full bioactivity via inhibition of the prolif-
eration of hepatic cancer cells [69]. Undoubtedly, these
studies demonstrate that these pH-responsive drug deliv-
ery platforms may be promising therapeutic agents for
enhancing TACE therapy for HCC treatment.
Functionalized embolic agent
Embolization is one of the essential steps in the TACE
procedure. Multifunctional nanoplatforms have been
developed as an embolization system to facilitate tran-
scatheter embolization. At present, there are many mate-
rials used for vascular embolization [137]. Usually, the
embolic agents used for TAE of HCC in clinical practice
include granular embolic agents represented by micro-
spheres and liquid embolic agents represented by lipiodol
[12, 14]. These embolic agents enter the tumor blood
Yuan et al. Journal of Nanobiotechnology (2023) 21:68
supply artery through the hepatic artery via the catheter
to achieve embolization by blocking the tumor’s blood
supply. Like these agents, multifunctional nanoplatforms
can also be developed as solid embolization systems (e.g.,
microsphere complexes) or fluid embolization systems
(e.g., hydrogel) to achieve embolization.
Solid embolization system
As a commonly used solid embolic agent of TACE in
clinical practice, microspheres are widely used in treating
HCC [14]. Increasing evidence shows that drug-eluting
microspheres have obvious advantages in reducing sys-
temic side effects of chemotherapy drugs [26, 138]. The
multifunctional nanoplatform developed by incorporat-
ing nanoparticles into microspheres can be used as an
embolic agent to promote transcatheter embolization. As
shown in Fig. 5, a multifunctional composite microsphere
(ADM/Fe3O4-MS) is synthesized by incorporating ADM
and ­Fe3O4 NPs into gelatin with a high-voltage electro-
spray technology [60]. In addition to having an excellent
embolization effect, it can disintegrate and release the
drug ADM and F ­ e3O4 NPs under microwave stimulation
in vitro. ­Fe3O4 NPs can provide excellent T2-weighted
MRI performance and significantly enhance the anti-
cancer effect via ferroptosis under microwave-induced
hyperthermia. In vitro and in vivo studies showed that
the multifunctional embolization system had significantly
better anti-tumor efficacy than other microspheres. To
promote transcatheter embolization, another research
developed a biodegradable multifunctional porous
microsphere (BMPM) composed of carrageenan (Addi-
tional file 1: Fig. S3), whose good roundness and excellent
Fig. 5 Schematic diagram of the preparation process of ADM/Fe3O4-MS and its TACE treatment mode. Reproduced with permission from Chen
et al. [60]. Copyright 2022, BMC
Page 11 of 21
swelling behavior guarantee them to be smoothly trans-
ported into targeted arteries’ ends and achieve satisfac-
tory embolization effect [53].
Although the microspheres as embolic agents have
many advantages in TACE application, it is challenging
to deliver the anti-cancer drug into tumor tissue for the
micron-sized embolic microspheres due to the physi-
ological barriers posed by the remarkably abnormal TME
to medication delivery. To solve these problems, Li et al.
developed a novel multifunctional embolic microsphere
with micro-nano binary progressive structure (MN-Ms)
for TACE applications [48]. As expected, a better anti-
tumor effect for MN-Ms was obtained by embolizing the
tumor-feeding arterial vessels, delivering chemothera-
peutic drugs to the targeted tumor tissue, and inhibiting
the reestablishment of collateral circulation.
Fluid embolization system
Currently, liquid embolic agents are at the forefront of
chemoembolization development because they allow
deeper penetration of tumor blood vessels, increase
tumor exposure to therapeutic drugs, and prevent revas-
cularization by occupying the vasculature of various
diameters, which is different from solid embolic parti-
cles [24]. Lipiodol is the first liquid embolic agent used in
TACE therapy, with a history of decades. Lipiodol-based
c-TACE is a common approach for treating middle and
agents on the market, Onyx® (Medtronic plc) and PHIL™
advanced HCC [11]. There are two other liquid embolic
(MicroVention, Inc.), which are mainly applied to embo-
lize intracranial and peripheral arteriovenous malforma-
tions (AVMs) [139, 140]. As these embolic agents often
Yuan et al. Journal of Nanobiotechnology (2023) 21:68 Page 12 of 21

need to be dissolved in DMSO for clinical application, it
is risky that they may induce vascular inflammation and
angionecrosis [141]. Moreover, neither Onyx nor PHIL
can be used to deliver drugs as the dissipation of DMSO
during administration would cause a burst release of the
entire therapeutic payload, resulting in acute local tox-
icity and transient therapeutic effects. Therefore, these
embolic agents cannot be used as chemoembolic agents
for TACE [24].
Although no other liquid embolization agent for TACE
except for lipiodol has been developed in clinical, some
drug-loaded liquid embolization systems, which can
be applied through intratumor or TACE-based intraar-
terial injection, have been studied in vitro and in vivo
with considerable breakthroughs [23, 68, 69]. As shown
in Fig. 6, Lym et al. developed a novel sulfamethazine-
based hydrogel, an anionic pH-sensitive block copoly-
mer named PCL-PEG-SM, with potential application
as a radiopaque embolic material [69]. Unlike lipiodol,
this liquid embolization agent can not only be injected
directly intratumor or perfused intraarterial after load-
ing chemotherapy drugs but also show a remarkable
sol–gel phase transformation to form a solidified state
once delivered to the tumor site, thus effectively blocking
the nutrient supply to tumor tissue (Fig. 6). In addition,
incorporating iodine-containing contrast agents into the
delivery system can also achieve real-time imaging moni-
toring during tumor treatment and postoperative imag-
ing follow-up of the tumor lesions.
Undoubtedly, these studies show that the multifunc-
tional nanoplatform plays a positive role in improving the
embolization efficiency of tumor vessels as an emboliza-
tion system.
Synergistic therapies
Chemo‑photothermal therapy
Ablation, such as radiofrequency or microwave abla-
tion, is a minimally invasive treatment based on thermal
effects, which has been clinically recognized as a radical
method for HCC [1]. However, these methods can only
be applied to the early stage of HCC [142]. Nanomateri-
als with thermal effects are not limited by tumor stage in
the application, and a hybrid embolization system can
be developed to satisfy both TACE therapy and thermal
ablation to maximize the treatment of tumor tissue. As
a synergistic therapeutic strategy, chemo-photothermal
systems based on nanomaterials have shown unique
advantages in HCC. Figure 7 illustrates the preparation
of a drug-loaded chemo-photothermal system and syner-
gistic therapy mechanism for HCC. The DOX-encapsu-
lated and near-infrared (NIR)-responsible copper sulfide
(CuS)-based (DOX@BSA-CuS) nanotherapeutics were
developed for MRI-guided chemo-photothermal therapy
of orthotopic HCC tumors in rats [76]. The as-prepared
BSA-CuS NPs exhibited more substantial absorbance in
the NIR region and photothermal effect to kill cancer
cells efficiently. Besides, the external NIR laser-induced
heating triggered the release of DOX synchronously.

Fig. 6 The in vivo gelation ability of the radiopaque embolic solutions, which contain copolymer (25 wt%), l­ipiodol® (10 wt%) and DOX
(10 mg ­mL−1), was observed at 5 h after injection. The white color of the radiopaque signals in red circles on CT images (A, B) and the red regions in
white circles or indicated arrows in the excised tumors images (C, D) indicated the gelation of the radiopaque embolic materials after intratumoral
(A, C) or intraarterial (B, D) injection. E H&E-stained histology image of excised tumor at 5 h after intraarterial injection in which the gel regions were
indicated by arrows. Reprinted with permission from Lym et al. [69]. Copyright 2016, Elsevier
Yuan et al. Journal of Nanobiotechnology (2023) 21:68
Fig. 7 Schematic illustration of DOX@BSA-CuS NP preparation and synergistic therapy of orthotopic liver cancer by chemo-photothermal
treatment through an intra-arterial intervention administration process. Reprinted with permission from Li et al. [76]. Copyright 2021, Elsevier
Furthermore, the DOX@BSA-CuS and lipiodol were
transarterially perfused through a catheter to simulta-
neously deliver chemotherapy and phototherapy locally
and ablate the tumor, synergistically playing the optimal
treatment effect (Fig. 7).
With the development of nanotechnology, more and
more chemo-photothermal systems such as DOX-
loaded α-Fe2O3@PDA [74], DOX-loaded SPION@PDA
[54], DOX@HAuNS [63], and UiO-66/Bi2S3@DOX [75]
have been developed for the treatment of HCC. In addi-
tion, magnetic nanoparticles (MNPs) have been devel-
oped for chemo-photothermal therapy owing to their
unique magnetic hyperthermia [60, 143]. A recent study
designed a novel magnetic drug carrier system consisting
of micron iron powder, barium ferrite ­(BaFe12O19) and
carbon-coated iron nanocrystals (CCIN). After magneti-
zation, ­BaFe12O19 can simultaneously adsorb CCIN and
iron powder to form large clusters. Under the effect of
the medium-frequency magnetic induction device, the
magnetic induction temperature can reach 43 °C within
1 min, and the highest temperature can reach 70.8 °C
Page 13 of 21
within 2.5 h [144]. These multifunctional NPs carrier
systems can simultaneously achieve multiple therapeu-
tic effects of enhanced chemotherapy, embolization, and
thermal ablation, which are expected to become a new
method for treating HCC.
Sensitizing lipiodol‑TACE
Lipiodol is not only a classical embolization agent but
also an ideal X-ray contrast agent. Although it faces the
drawbacks of rapid drug release and unstable proper-
ties of lipiodol emulsions in c-TACE treatment process
[145], it still plays a vital role in the chemoembolization
of HCC.
Several approaches have been devoted to improving
the stability of hydrophilic chemotherapeutic drugs in
lipiodol [49, 66, 67, 146]. The combination of nanocar-
rier with lipiodol-TACE in treating HCC can synergis-
tically enhance the therapeutic effect of c-TACE. Shen
et al. developed a new type of “oil-soluble” nanocarriers,
named reversed lipid-based NPs (RLBNs), for the deliv-
ery of DOX, which was dispersed in lipiodol for TACE
Yuan et al. Journal of Nanobiotechnology (2023) 21:68 Page 14 of 21

treatment of rat liver cancer. Compared with c-TACE
system, this nanocarrier embolization system possesses
a hydrophobic nanostructure with a high dispersibility in
oils, significantly sustained drug release characteristics,
lower side effects, and significantly enhanced inhibition
of tumor growth [49]. Another attractive approach to
stabilizing lipiodol emulsion is to use Pickering technol-
ogy to obtain biodegradable, remarkably stable water-in-
oil (W/O) lipiodol emulsion by adding PLGA NPs into
the aqueous-phase of the formulation and emulsifying
the solution using two connected syringes [67]. Com-
pared with usual emulsions stabilized with synthetic sur-
factants, this W/O Pickering emulsion stabilized with
these NPs has the advantage of being biodegradable, bio-
compatible, and less toxic.
Furthermore, a carrier-free hydrophilic drug nano-
technology-based super-stable homogeneous intermixed
formulation (SHIFT) system was developed to overcome
the lack of physical stability of TACE development [147,
148]. As shown in Fig. 8, the DOX solution was prepared
as a pure nanodrug and then stably and homogeneously
dispersed in lipiodol (SHIFT&DOX) by slightly ultra-
sonic dispersion. In vivo results showed that, unlike the
conventional mixture of DOX and lipiodol, SHIFT&DOX
exhibited excellent prolonged drug retention and sus-
tained drug release effect in tumor lesions, which pro-
vided a promising approach to solving the instability of
the traditional lipiodol emulsion and sensitizing the ther-
apeutic effect of lipiodol-TACE in clinic [146].
Research status of nanomaterial for TACE therapy
in the treatment of HCC
Clinical researches
Although ablation, surgery, and liver transplantation are
radical treatments for HCC, the outlook suggests that
new nano-conditioned therapies based on TACE will be
helpful in clinical practice [72]. Researchers have set the
goal of developing nanoplatforms to apply nanomaterials
in clinics so as to improve the efficacy of TACE in treat-
ing HCC and reduce systemic side effects.
As early as 2006, Dudeck et al. sought to prove the
feasibility of selective arterial infusion of SPIO particles
in patients with HCC; all patients underwent MRI as
a baseline and immediate follow-up investigation [50].
Although only 13 cases were included, this study laid
the foundation for using SPIO NPs in the treatment of
HCC by TACE. Recently, a study explored the value of
TACE combined with a targeted NPs delivery system for
sorafenib (SFB) to treat HCC with microvascular inva-
sion [97]. 42 HCC patients with microvascular invasion
after liver cancer surgery were divided into an experi-
mental group (18 cases treated with combination therapy
of TACE and Ab-SFB-NP system) and a control group
(24 cases who took TACE and non-nano drug delivery
system) based on their willingness. The results showed
that these polymer NPs had high adoption value and high
security, which could become a new nanomedicine plat-
form for liver therapy, and patients with advanced HCC
who cannot be treated with surgery were given some

Fig. 8 Schematic illustration of SHIFT&DOX preparation and transarterial chemoembolization of HCC. A Superstable pure-nanomedicine
formulation technology (SPFT) was used to produce nano-DOX with a smaller nanoparticle size and homogeneity. B Subsequently, nano-DOX
was homogeneously dispersed into lipiodol via ultrasonication (US) to prepare the SHIFT&DOX. C The SHIFT&DOX was specifically deposited into
hepatocellular carcinoma lesions through transcatheter embolization. This led to long-term DOX stability and slow drug release from lipiodol to
improve treatment effects and safety of HCC. Reproduced with permission from He et al. [146]. Copyright 2022, Ivyspring
Yuan et al. Journal of Nanobiotechnology (2023) 21:68
hope of survival. In addition, as a common nanocarrier,
liposomes have also shown apparent advantages in the
TACE delivery system. By encapsulating DOX within a
liposome of polyethylene glycol (PEG), PEGylated lipo-
somal DOX (PGLD) can reduce DOX toxicity and block
the drug recognized by the mononuclear macrophage
system, thus prolonging its circulation [149, 150]. Liao
et al. conducted a clinical study which revealed that com-
bined therapy with raltitrexed and PGLD in TACE could
alleviate adverse chemotherapy responses in patients
with HCC and improve overall survival (OS) [47].
Undoubtedly, although additional extensive, randomized
controlled studies are needed to evaluate the clinical
application value of these therapeutic approaches, the
results presented in these clinical studies have already
provided a promising palliative therapeutic option for
patients with unresectable HCC.
Basic experimental research
At present, although some single-center and small-scale
clinical studies have attempted to apply nanoplatforms
in the treatment of HCC by TACE and have achieved
encouraging results, it is worth noting that most of the
studies on the application of multifunctional nanoplat-
forms in TACE against HCC are still at the basic stage.
As shown in Table 4, animal models (such as rats, rabbits,
or swine) are still the main research subjects of nanoplat-
forms for the diagnosis and treatment of liver cancer. As
one of the most used animal models, rats are cheap in
price, easy to obtain, and relatively easy to model, so they
are widely used in studying nanoplatform imaging diag-
nosis, drug delivery, and PTT [52, 56, 61, 98]. Whereas,
due to the requirements of vascular size for interven-
tional intubation, the study of rat liver cancer models for
TACE is relatively rare. Currently, VX2 tumor-bearing
Table 4 Different models for the study of TACE treating HCC with nano-formulation
Species Models Characteristic
Human HCC patients Clinical trials, high level of
evidence
Rat N1S1 liver tumor; Low cost, easy to obtain, breed
Mca-rh7777 rat; and raise, relatively easy to
ACI rat (Morris hepatoma 3924A) modeling
Rabbit VX2 liver cancer; Similar pathological and ana-
rabbit ear embolization model tomic characteristics with HCC
patients, high reproductive, large
body size, and suitable for TACE
procedure
Swine Porcine (healthy); High homology to human, suit-
PBPK model able for interventional intubation image (X-ray);
PBPK porcine semi-physiologically based pharmacokinetic
Page 15 of 21
rabbits remain excellent animal models for studying
TACE therapy for HCC. Although the VX2 tumor is
not hepatogenic, the rabbit VX2 liver tumor model has
similar pathological and anatomic characteristics with
HCC patients, especially since the tumor’s blood sup-
ply is very similar to that of HCC. Thus, this model is a
classic animal model for interventional embolization of
HCC, which plays a crucial role in studying the applica-
tion of multifunctional nanoplatforms in TACE therapy
of HCC [39, 58, 65, 78, 151–153]. In addition, apart from
the above two animal models, the swine model is also
considered suitable for TACE study as it has the advan-
tages of high homology to humans and is suitable for
interventional intubation. However, it has not yet been
widely used since the high cost and complexity of mod-
eling, and only a few studies have conducted feasibility
demonstration studies on transarterial intubation, imag-
ing, and pharmacokinetics in healthy porcine models [36,
154, 155].
Limitations
Obviously, numerous studies have shown that apply-
ing multifunctional nanoplatforms in TACE therapy for
HCC has made great progress. However, some bottleneck
problems restricting the efficacy of TACE still need to be
further solved. (1) While multifunctional nanoplatforms
endow nanomaterials with multiple functions, it inevita-
bly needs to incorporate more substances, and the mate-
rial safety issue brought by this is still a huge challenge
for researchers. (2) A series of changes in TME after
TACE, such as accumulation of acid metabolic products,
hypoxia-induced angiogenesis, resistance, and autophagy
activation, restrict the efficacy of TACE therapy. There-
fore, how to deal with the changes in these microenvi-
ronments after tumor embolization is still the focus of
Research field Refs.
Image (MRI); [47, 50, 51, 97]
drug delivery
Image (MRI); drug deliver; [49, 52, 53, 56, 61, 74–76, 96, 98,
embolization; 146]
PTT, targeting therapy
Image (US, X-ray, MRI); drug [36, 54, 55, 57–60, 62–66, 68, 69, 78,
deliver; embolization; 107, 113, 146, 156]
gene therapy; PTT; PDT; micro-
wave ablation
Embolization; [36, 154, 155]
pharmacokinetic profiles; drug
deliver
Yuan et al. Journal of Nanobiotechnology (2023) 21:68
researches and it encourages researchers to develop new
nanoplatforms. (3) Imaging follow-up after tumor embo-
lization is essential for evaluating the therapeutic effect.
At present, there is still a lack of stable and effective
imaging follow-up nanoplatforms; therefore, developing
multifunctional nanoplatforms capable of image follow-
up for TACE therapy is urgent. In short, there is still a
long way to go for multifunctional nanoplatforms from
basic research to clinical application, and only continu-
ous innovation can achieve breakthroughs.
Conclusions and perspectives
Recent studies on the improvement of TACE nanoma-
terials are very promising. Based on the review of previ-
ous relevant studies, we believe that the most significant
advantage of multifunctional nanoplatforms in TACE
treatment of HCC is that it can not only improve the
distribution of chemotherapy drugs in local tumor tis-
sues but also avoid the serious side effects caused by
systemic drug administration. Moreover, with special
physical and chemical properties, the nanoplatforms can
be combined with TACE to play a synergistic anticancer
role and enhance the therapeutic effect. The minimally
invasive interventional technique dramatically improves
nanocarriers’ tumor targetability and antitumor efficacy.
Improvements in the therapeutic effect of TACE may
be possible via the development of new multifunctional
nanoplatforms with properties such as detectability with
imaging, targetability, efficient delivery and emboliza-
tion, biodegradability, and the incorporation of multiple
therapeutics or multiple therapeutic modalities. Besides,
more choices are available for applying new nanoplat-
forms in TACE for the precise therapy of HCC with rapid
development of nanomaterials and significant progress
in nanotechnology. However, most studies of multifunc-
tional nanoplatform were only carried out in animal
models and have not yet been applied to large-scale in
vivo studies in patients. Therefore, more efforts such as
preclinical studies of the biosafety and anticancer effi-
cacy of nanoformulations as drug carriers are still eagerly
needed to pave the way for the translation of new nan-
oformulations into clinical use and thus to improve the
overall patient outcome of HCC treatment. On the other
hand, nanotechnology and transcatheter arterial emboli-
zation techniques in animals do not seem to fully realize
their potential so far. The underlying applications in each
field still need to be developed.
In conclusion, although the multifunctional nano-
platforms have not yet been widely used in clinical
practice, and some thorny issues that limit the effi-
cacy of TACE also need to be solved urgently, these
studies have undoubtedly provided a broader vision
Page 16 of 21
for clinical TACE treatment of HCC. In addition, the
potential of some emerging cancer treatments based
on nanomedicine, such as chemodynamic therapy
(CDT) [157], molecular dynamic therapy (MDT) [158],
and immunotherapy [159], provides more new oppor-
tunities and challenges for researchers to develop
some innovative multifunctional nanoplatforms to
improve the efficacy of TACE in the treatment of
HCC. The design concepts, functional characteristics,
and therapeutic effects of these nanoplatforms pro-
vided reference for developing more appropriate and
effective embolization materials. Therefore, based on
these previous studies, it is highly expected that some
novel multifunctional nanoplatforms with higher effi-
cacy and safety will be developed and applied in the
TACE therapy of HCC.
Abbreviations
HCC Hepatocellular carcinoma
TACE Transarterial chemoembolization
BCLC Barcelona clinic liver cancer
DEBs Drug-eluting beads
DOX Doxorubicin
NPs Nanoparticles
FDA Food and Drug Administration
SFB Sorafenib
ECM Extracellular matrix
P-gp P-glycoprotein
HA Hyaluronic acid
HACE Hyaluronic Acid-ceramide (HACE)
VEGF Vascular endothelial growth factor
EPR Enhanced permeability and retention
PAH Polyallylamine hydrochloride
PAA Polyacrylic acid
CPPs Cell-penetrating Peptides
TME Tumor microenvironment
CCIN Carbon-coated iron nanocrystals
RLBNs Reversed Lipid-based NPs (RLBNs)
SHIFT Super-stable homogeneous intermixed formulation
Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12951-​023-​01820-7.
Additional file 1: Fig. S1 Schematic illustration showing the use of newly
developed DOX-NPs-MB complex in lipiodol formulation to enhance drug
delivery via ultrasound irradiation (US+) during TACE procedure. Repro-
duced with permission from Kim et al [1]. Copyright 2021, Ivyspring. Fig.
S2 Schematic illustration of drug loading, cellular entry, drug release, and
antitumor mechanism of LHD/miR-375. Reproduced with permission from
Xue et al [2]. Copyright 2017, Dove Medical Press. Fig. S3 A brief introduc-
tion about BMPMs’ ingredients, structure as well as working mechanism
on iTACE. Reproduced with permission from Liu et al [3]. Copyright 2020,
Elsevier.
Acknowledgements
We thank Dr. Li Liu (School of Foreign Languages, Southwest Medical Univer-
sity) for her English language editing assistance, Dr. Xiao-ming Zhu (Macau
University of Science and Technology), and Prof. Yan-zheng He (Southwest
Medical University) for their theoretical direction assistance.
Yuan et al. Journal of Nanobiotechnology (2023) 21:68
Author contributions
GY, Z-YL, W-MW, and YL proposed the concept and constructed the framework
of the article. Y-NX, M-NL and XZ searched and collected literatures. WH, YF
and G-YS wrote and revised the manuscript. GY and Y-NX drew figures. All
authors read and approved the final manuscript.
Funding
This work was supported by the Beijing Medical Award Foundation (YXJL-
2020–0972-0426), the Foundation of Science and Technology Department of
Sichuan Province (Miao Zi Project, No. 2022095), Luzhou Science and Technol-
ogy Plan Project (No. 2022-JYJ-153), and the Natural Science Foundation of
Southwest Medical University [2022QN114].
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Received: 17 November 2022 Accepted: 15 February 2023
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