Liver cancer, notably hepatocellular carcinoma (HCC), poses a significant global health burden due to its high fatality rates. Conventional antitumor medications face challenges, including poor targeting, high toxicity, and drug resistance, leading to suboptimal clinical outcomes. This review focused on nanoparticle use in diagnosing and delivering medication for HCC, aiming to advance the development of nanomedicines for improved treatment outcomes. As an emerging frontier science and technology, nanotechnology has shown great potential, especially in precision medicine and personalized treatment. The success of nanosystems is attributable to their smaller size, biocompatibility, selective tumor accumulation, and lower toxicity. Nanoparticles, as a central part of nanotechnology innovation, have emerged in the field of medical diagnostics and therapeutics to overcome the various limitations of conventional chemotherapy, thus offering promising applications for improved selectivity, earlier and more precise diagnosis of cancers, personalized treatment, and overcoming drug resistance. Nanoparticles play a crucial role in drug delivery and imaging of HCC, with the body acting as a delivery system to target and deliver drugs or diagnostic reagents to specific organs or tissues, helping to accurately diagnose and target therapies while minimizing damage to healthy tissues. They protect drugs from early degradation and increase their biological half-life.

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.

Long non-coding RNAs (Lnc RNAs) are proven to participate in liver cancer (LC) regulation. The regulation of miR-21 by lnc NBAT1 has been studied in other cancers. However, the effect of this regulation on LC and its specific mechanism remains unclear. Lnc NBAT1 and miR-21 expressions in clinical tissues were measured by RT-qPCR. PDCD4, AP-1, p-c-Fos, p-c-Jun, and cyclin D1 expressions were analyzed by Western blot. Overexpression of lnc NBAT1 was studied to explore its influence on malignant behaviors of Bel7402 cells and the development of LC in the xenograft mouse model (XMM). The regulation mechanism of lnc NBAT1 in LC was explored by lnc NBAT1 overexpression, miR-21 mimic treatment, or PDCD4 silencing in Bel7402 cells. Lnc NBAT1 expression was downregulated while miR-21 expression was upregulated in LC tissues and cell lines. In comparison with LX-2 cells, the expressions of PDCD4 and AP-1 were downregulated in Bel7402 cells, while those of p-c-Fos, p-c-Jun, and cyclin D1 were upregulated. Further, lnc NBAT1 was found to localize primarily in the cytoplasm of Bel7402 cells. Overexpression of lnc NBAT1 enhanced cell apoptosis, blocked the cell cycle, suppressed malignant behaviors of Bel7402 cells, and inhibited tumor progression in the XMM. Mechanistically, lnc NBAT1 functioned as a competing endogenous RNA (ceRNA) by binding to the downstream target miR-21 to stabilize the expressions of PDCD4 and AP-1, thereby inhibiting malignant behaviors of Bel7402 cells. Lnc NBAT1 suppressed malignant behaviors of LC cells through the miR-21/PDCD4/AP-1 axis. Lnc NBAT1 might be a promising biomarker for LC treatment.

The pathogenesis exploration and timely intervention of hepatocellular carcinoma (HCC) are crucial due to its global impact on human health. As a general tumor biomarker, stanniocalcin 2 (STC2), its role in HCC remains unclear. We aimed to analyze the effect and mechanism of STC2 on HCC.

STC2 expressions in HCC tissues and cell lines were measured. si-STC2 and oe-STC2 transfections were utilized to analyze how STC2 affected cell functions. Functional enrichment analysis of STC2 was performed by Gene Set Enrichment Analysis (GSEA). The regulatory mechanism of STC2 on HCC was investigated using 2-DG, 3-MA, IGF-1, Rap, and LY294002. The impact of STC2 on HCC progression in vivo was evaluated by the tumor formation experiment.

Higher levels of STC2 expression were observed in HCC tissues and cell lines. Besides, STC2 knockdown reduced proliferation, migration, and invasion, while inducing cell apoptosis. Further analysis indicated a positive correlation between STC2 and glycolysis. STC2 knockdown inhibited glycolysis progression and down-regulated the expressions of PKM2, GLUT1, and HK2 in HCC cells. However, treatment with glycolysis inhibitor (2-DG) prevented oe-STC2 from promoting the growth of HCC cells. Additionally, STC2 knockdown up-regulated the levels of LC3II/LC3I and Beclin1 and reduced the phosphorylation of PI3K, AKT, and mTOR. Treatment with 3-MA, IGF-1, Rap, and LY294002 altered the function of STC2 on proliferation and glycolysis in HCC cells. Tumor formation experiment results revealed that STC2 knockdown inhibited HCC progression.

STC2 knockdown inhibited cell proliferation and glycolysis in HCC through the PI3K/Akt/mTOR pathway-mediated autophagy induction.

Transcatheter arterial embolization (TAE) in interventional therapy and tumor embolism therapy plays a significant role. The choice of embolic materials that have good biocompatibility is an essential component of TAE. For this study, we produced a multifunctional PVA embolization material that can simultaneously encapsulate Ag2S quantum dots (Ag2S QDs) and BaSO4 nanoparticles (BaSO4 NPs), exhibiting excellent second near-infrared window (NIR-II) fluorescence imaging and X-ray imaging, breaking through the limitations of traditional embolic microsphere X-ray imaging. To improve the therapeutic effectiveness against tumors, we doped the doxorubicin (DOX) antitumor drug into microspheres and combined it with a clotting peptide (RADA16-I) on the surface of microspheres. Thus, it not only embolizes rapidly during hemostasis but also continues to release and accelerate tumor necrosis. In addition, Ag2S/BaSO4/PVA microspheres (Ag2S/BaSO4/PVA Ms) exhibited good blood compatibility and biocompatibility, and the results of embolization experiments on renal arteries in rabbits revealed good embolic effects and bimodal imaging stability. Therefore, they could serve as a promising medication delivery embolic system and an efficient biomaterial for arterial embolization. Our research work achieves the applicability of NIR-II and X-ray dual-mode images for clinical embolization in biomedical imaging.

Transarterial chemoembolization (TACE) is widely recognized as a non-surgical treatment approach for advanced liver cancer, combining chemotherapy with the blockage of blood vessels supplying the tumor. To enhance the efficacy of TACE and address chemotherapy resistance, there is growing interest in the development of multifunctional embolic microspheres. In this study, multifunctional PVA microspheres, which encapsulate MIT as a chemotherapeutic drug, PPY as a photothermal agent, and Fe3O4 as a chemodynamic therapy agent, were prepared successfully. The results demonstrated that the developed multifunctional PVA microspheres not only exhibit favorable drug release, photothermal therapy, and chemodynamic therapy performance, but also show a promising synergistic therapeutic effect both in vitro and in vivo. Consequently, the engineered multifunctional PVA microspheres hold tremendous promise for enhancing TACE effectiveness and have the potential to overcome limitations associated with traditional liver cancer treatments.

Tumor hypoxia-associated drug resistance presents a major challenge for cancer chemotherapy. However, sustained delivery systems with a high loading capability of hypoxia-inducible factor-1 (HIF-1) inhibitors are still limited. Here, we developed an ultrastable iodinated oil-based Pickering emulsion (PE) to achieve locally sustained codelivery of a HIF-1 inhibitor of acriflavine and an anticancer drug of doxorubicin for tumor synergistic chemotherapy. The PE exhibited facile injectability for intratumoral administration, great radiopacity for in vivo examination, excellent physical stability (>1 mo), and long-term sustained release capability of both hydrophilic drugs (i.e., acriflavine and doxorubicin). We found that the codelivery of acriflavine and doxorubicin from the PE promoted the local accumulation and retention of both drugs using an acellular liver organ model and demonstrated significant inhibition of tumor growth in a 4T1 tumor-bearing mouse model, improving the chemotherapeutic efficacy through the synergistic effects of direct cytotoxicity with the functional suppression of HIF-1 pathways of tumor cells. Such an iodinated oil-based PE provides a great injectable sustained delivery platform of hydrophilic drugs for locoregional chemotherapy.

Lipiodol-based transcatheter arterial chemoembolization (TACE) is currently the predominant and first-line treatment option recommended by the global standard for unresectable hepatocellular carcinoma (HCC). However, the unstable emulsion of Lipiodol causes a substantial proportion of chemotherapy drugs to enter the circulation system, leading to poor accumulation in cancer tissues and unexpected side effects of chemotherapy drugs. Herein, we emulsified Lipiodol with a pH-sensitive drug delivery system assembled from hexahistidine and zinc ions (HmA) with a super-high loading capacity of doxorubicin (DOX) and a promising ability to penetrate bio-barriers for the effective treatment of HCC by TACE. In vitro tests showed that DOX@HmA was comparable to free DOX in killing HCC cells. Impressively, during the in vivo TACE treatment, the anti-tumor efficacy of DOX@HmA was significantly greater than that of free DOX, indicating that DOX@HmA increased the accumulation of DOX in tumor. Emulsifying Lipiodol with pH-sensitive DOX@HmA significantly inhibited cell regeneration and tumor angiogenesis and decreased the systemic side effects of chemotherapy, especially by suppressing pulmonary metastasis in liver VX2 tumors in rabbits by inhibiting epithelial-mesenchymal transition (EMT). Emulsifying tumor microenvironment-responsive drug delivery systems (DDSs) with Lipiodol could be a new strategy for clinical TACE chemotherapy with potentially enhanced HCC treatment.

An embolic reagent with easy injection, well-controlled target embolization, and sustained release of chemotherapy drugs is urgently needed for successful trans-arterial chemo-embolization (TACE) treatment. However, the development of a highly effective embolic reagent is still challenged. Here, inspired and guided by the structural supporting properties and defense mechanisms of wood cell walls, an ideal lignin-based embolic nanogel (DOX-pN-KL) was explored. Based on the mechanical support of branched lignin and the π-π stacking force between the lignin aromatic ring with anti-tumor drug doxorubicin (DOX), DOX-pN-KL showed the highest mechanical strength among the reported thermosensitive embolization nanogel and performed high drug-loading and favorable sustained-release. Moreover, further TACE treatment and tumor microenvironment evaluation of VX2 tumor-bearing rabbits showed that this nanogel can completely block all levels of vessels in long term and continuously release DOX, thus having effective inhibition on tumor growth and metastasis. DOX-pN-KL is expected to be a promising alternative reagent for interventional therapy.

Hepatocellular carcinoma (HCC) is one of the cancers that has the highest morbidity and mortality rates. In clinical practice, there are still many limitations in surveilling, diagnosing, and treating HCC, such as the poor detection of early HCC, the frequent post-surgery recurrence, the low local tumor control rate, the therapy resistance and side effects. Therefore, improved, or innovative modalities are urgently required for early diagnosis as well as refined and effective management. In recent years, nanotechnology research in the field of HCC has received great attention, with various aspects of diagnosis and treatment including biomarkers, ultrasound, diagnostic imaging, intraoperative imaging, ablation, transarterial chemoembolization, radiotherapy, and systemic therapy. Different from previous reviews that discussed from the perspective of nanoparticles' structure, design and function, this review systematically summarizes the methods and limitations of diagnosing and treating HCC in clinical guidelines and practices, as well as nanomedicine applications. Nanomedicine can overcome the limitations to improve diagnosis accuracy and therapeutic effect via enhancement of targeting, biocompatibility, bioavailability, controlled releasing, and combination of different clinical treatment modalities. Through an in-depth understanding of the logic of nanotechnology to conquer clinical limitations, the main research directions of nanotechnology in HCC are sorted out in this review. It is anticipated that nanomedicine will play a significant role in the future clinical practices of HCC.

Transcatheter arterial chemoembolization (TACE) is extensively used in the treatment of hepatocellular carcinoma (HCC), but its efficacy is usually limited to secondary tumor hypoxia and other progressive exacerbation of the abnormal tumor microenvironment (TME). Herein, we synthesized polyvinyl pyrrolidone (PVP)-coated CaO₂ nanoparticles (CaO₂ NPs) and applied them as a synergistic agent to improve the antitumor efficacy of TACE. After injection into the tumor, CaO₂ NPs reacted with water to generate abundant oxygen, hydroxyl ions (OH^-), and calcium ions (Ca²⁺), thereby relieving tumor hypoxia, neutralizing acid, and overloading Ca²⁺ to mediate antitumor effects. Moreover, the effect of chemotherapeutic drugs within the TACE was improved due to the modulated TME. CaO₂ NPs efficiently regulated the TME and improved the antitumor effect of doxorubicin under hypoxia conditions in vitro. Compared to other groups, the TACE+CaO₂ NPs group achieved the lowest tumor growth rate, highest tumor necrosis rate, lowest expression of histological markers associated with hypoxia and angiogenesis (HIF-α, VEGF, and CD31), and highest CD8⁺ T cell recruitment in vivo. Thus, these findings demonstrated that CaO₂ NPs provide synergy for TACE therapy in the VX2 orthotopic rabbit liver cancer model, suggesting that they have a potential broad clinical application. STATEMENT OF SIGNIFICANCE: The efficacy of transcatheter arterial chemoembolization (TACE) for treatment of hepatocellular carcinoma is usually limited to secondary tumor hypoxia and other progressive exacerbation of the abnormal tumor microenvironment (TME). To address this issue, we synthesized CaO₂ nanoparticles (CaO₂ NP_S) which would react with water to generate abundant oxygen, hydroxyl ions (OH^-), and calcium ions (Ca²⁺), thereby relieving tumor hypoxia, neutralizing the acidic TME, and inducing Ca²⁺ overloading. The efficacy of CaO₂ NPs in combination with TACE was investigated in an orthotopic rabbit liver cancer model, and the results showed the great synergetic antitumor effect of TACE and CaO₂ NPs.

Primary liver cancer is the seventh-most-common cancer worldwide and the fourth-leading cause of cancer mortality. In the current era of precision medicine, the diagnosis and management of liver cancer are full of challenges and prospects. Mesoporous nanoparticles are often designed as specific carriers of drugs and imaging agents because of their special morphology and physical and chemical properties. In recent years, the design of the elemental composition and morphology of mesoporous nanoparticles have greatly improved their drug-loading efficiency, biocompatibility and biodegradability. Especially in the field of primary liver cancer, mesoporous nanoparticles have been modified as highly tumor-specific imaging contrast agents and targeting therapeutic medicine. Various generations of complexes and structures have been determined for the complicated clinical management requirements. In this review, we summarize these advanced mesoporous designs in the different diagnostic and therapeutic fields of liver cancer and discuss the relevant advantages and disadvantages of transforming applications. By comparing the material properties, drug-delivery characteristics and application methods of different kinds of mesoporous materials in liver cancer, we try to help determine the most suitable drug carriers and information media for future clinical trials. We hope to improve the fabrication of biomedical mesoporous nanoparticles and provide direct evidence for specific cancer management.

Transarterial chemoembolization (TACE) with free doxorubicin-lipiodol emulsions (free DOX/L) is a favored clinical treatment for advanced hepatocellular carcinoma (HCC) patients ineligible for radical therapies; however, its inferior colloidal stability not only greatly reduces its tumor retention but also hastens drug release into blood circulation, leading to suboptimal clinical outcomes. Here, we find that disulfide-crosslinked polymersomes carrying doxorubicin (Ps-DOX) form super-stable and homogenous water-in-oil microemulsions with lipiodol (Ps-DOX/L). Ps-DOX/L microemulsions had tunable sizes ranging from 14 to 44 μm depending on the amount of Ps-DOX, were stable over 2 months storage as well as centrifugation, and exhibited nearly zero-order DOX release within 15 days. Of note, Ps-DOX induced 2.3-13.4 fold better inhibitory activity in all tested rat, murine and human liver tumor cells than free DOX likely due to its efficient redox-triggered intracellular drug release. Interestingly, transarterial administration of Ps-DOX/L microemulsions in orthotopic rat N1S1 syngeneic HCC model showed minimal systemic DOX exposure, high and long hepatic DOX retention, complete tumor elimination, effective inhibition of angiogenesis, and depleted adverse effects, significantly outperforming clinically used free DOX/L emulsions. This smart polymersome stabilization of doxorubicin-lipiodol microemulsions provides a novel TACE strategy for advanced tumors.

This study aims to discover the therapeutic effect of chemokine (CXC motif) receptor 4 (CXCR4) antagonist AMD3100 combined with transcatheter arterial chemoembolization (TACE) in a rat model with hepatocellular carcinoma (HCC). An orthotopic model of HCC was established and treated with TACE (doxorubicin-lipiodol emulsion) with or without AMD3100. The tumor volume was measured by magnetic resonance imaging (MRI). Histopathological changes were detected by hematoxylin-eosin (HE) staining. HCC cell apoptosis was assessed by terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labeling (TUNEL) staining. Immunohistochemistry was used to detect the expression of CD34, hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), and Ki67. Gene and protein expressions were quantified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting, respectively. Both TACE and AMD3100 reduced the tumor volume in orthotopic rat model of HCC with the decreased CXCR4 expression in tumor tissues, and the combination had better effect. However, TACE increased the microvessel density (MVD) in HCC tissues of rats, while AMD3100 treatment reduced MVD in HCC tissues. AMD3100 reduced the TACE induced MVD in HCC tissues with the reduction of HIF-1α and VEGF expression. Either AMD3100 or TACE could promote HCC cell apoptosis accompanying by decreased cell proliferation, and their combined use had better therapeutic effects. CXCR4 antagonist AMD3100 enhance therapeutic efficacy of TACE in rats with HCC via promoting the HCC cell apoptosis, reducing cell proliferation, and inhibiting MVD, thus reducing tumor volume.

Advances in nanozyme involve an efficient catalytic process, which has demonstrated great potential in tumor therapy. The key to improving catalytic therapy is to solve the limitation of the tumor microenvironment on Fenton reaction. In this work, Prussian blue nanoparticles doped with different rare earth ions (Yb³⁺, Gd³⁺, Tm³⁺) were screened to perform synergistic of photothermalandcatalytictumortherapy. The optimized catalytic performance can be further enhanced through photothermal effect to maximize the Fenton reaction to solve the limitation of the tumor microenvironment. Yb-PB, with the optimal photothermal and catalytic performance, was screened out. In order to avoid the scavenging effect of glutathione (GSH) on ·OH in tumor cells and the reaction with a bit H₂O₂ in normal cells, GSH targeted polydopamine (PDA) was wrapped on the surface of Yb-PB to obtain Yb-PB@PDA. It was found that enough hydroxyl radicals (·OH) can be generated even if at high GSH concentration and the NIR irradiation can help produce more ·OH. Cell fluorescence imaging (FOI) and in vivo magnetic resonance imaging (MRI) experiments showed the potential application in FOI/MRI dual-mode imaging guided therapy. In vivo anti-tumor experiments showed that Yb-PB@PDA has a satisfactory anti-cancer effect through the combined effect of catalytic/photothermal therapy. Thus, a multifunctional nanozyme for tumor therapy is constructed.

Hepatocellular carcinoma (HCC) is characterized by poor prognosis and high mortality. The treatment of HCC is closely related to the stage, and the early-stage of HCC patients usually accompanies a more long-term survival rate after clinical treatment. Hence, there are critical needs to develop effective imaging agents with superior diagnostic precision for HCC detection at an early stage. Recently, mesoporous silica nanoparticles (MSNs) based imaging agents have gained extensive attentions in HCC detection, which can serve as a multifunctional nanoplatform with controllable size and facile surface functionalization. This perspective summarizes recent advances in MSNs based imaging agents for HCC detection by the incorporation of several clinical imaging modalities. Multi-modal imaging system has been developed for higher spatial resolution and sensitivity. Even though some limitations and challenges need to be overcome, we envision the development of novel MSNs based imaging agents will offer great potential applications in clinical HCC detection.

CO₂ gas generating poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) was designed for rapid release of tanespimycin (17-AAG) in transarterial chemoembolization (TACE) treatment of hepatocellular carcinoma (HCC). As poorly water-soluble drug is generally released from PLGA MS in a sustained manner, the drug release profile should be controlled according to its clinical indications. In current study, responding to immediate increase in hypoxia inducible factor-1α (HIF-1α) level under hypoxia state followed by embolization of tumor feeding arteries, sodium bicarbonate (NaHCO₃) was added to PLGA/17-AAG MS for fast drug release by CO₂ gas generation in slightly acidic tumor microenvironment. With the aid of NaHCO₃, initial burst release of 17-AAG was available without losing the micron-size and spherical shape of designed MS for embolization of artery. Acid-responsive CO₂ gas generation and subsequent immediate release of 17-AAG from MS were successfully verified. PLGA/17-AAG/NaHCO₃ MS-treated group exhibited higher antiproliferation and apoptosis induction efficacies in McA-RH7777 and SNU-761 cells. McA-RH7777 tumor-implanted rats treated by TACE using PLGA/17-AAG/NaHCO₃ MS presented a complete therapeutic response. All these findings suggest that developed tumor microenvironment-responsive gas-generating MS can be efficiently applied to TACE therapy of HCC.

Cancer is one of the leading causes of mortality worldwide. Nanoparticles have been broadly studied and emerged as a novel approach in diagnosis and treatment of tumors. Over the last decade, researches have significantly improved magnetic nanoparticle (MNP)'s theranostic potential as nanomedicine for cancer. Newer MNPs have various advantages such as wider operating temperatures, smaller sizes, lower toxicity, simpler preparations and lower production costs. With a series of unique and superior physical and chemical properties, MNPs have great potential in medical applications. In particular, using MNPs as probes for medical imaging and carriers for targeted drug delivery systems. While MNPs are expected to be the future of cancer diagnosis and precision drug delivery, more research is still required to minimize their toxicity and improve their efficacy. An ideal MNP for clinical applications should be precisely engineered to be stable to act as tracers or deliver drugs to the targeted sites, release drug components only at the targeted sites and have minimal health risks. Our review aims to consolidate the recent improvements in MNPs for clinical applications as well as discuss the future research prospects and potential of MNPs in cancer theranostics.