Mapping research hotspots and trends in hepatocellular carcinoma nanomedicine: a bibliometric analysis

Abstract

Hepatocellular carcinoma (HCC) is a prevalent cancer globally with a poor prognosis. Nanomedicine applications are expected to enhance early detection, improve cytotoxic drug utilization, and improve HCC prognosis. This study aims to conduct a comprehensive bibliometric analysis of research on nanomedicines in HCC, focusing on current hotspots and exploring future development directions. By searching Web of Science, we collected 4,372 English-language articles from January 1, 2012 to October 31, 2022. China emerged as the leading contributor with 2,473 publications (55.6%), followed by the US (299, 6.8%) and India (284, 6.5%). Sun Yat-sen University had the highest number of publications. The most cited journal was the INTERNATIONAL JOURNAL OF NANOMEDICINE, and BIOMATERIALS was the most influential based on H/g/m indices. Key research areas included NANOPARTICLES (11% of keyword occurrences), HEPATOCELLULAR-CARCINOMA (8% ), and DRUG-DELIVERY (6%). in-vitro drug-delivery research remains a potential area. This study reveals that nanomedicines have significant potential in improving HCC early detection, drug-use efficiency, and prognosis. Encapsulating cytotoxic drugs in nanoparticles is a predominant research hotspot, while nanoparticle toxicity’s impact on human systems may be a promising future direction. These findings provide valuable insights for guiding future research and clinical translation in HCC nanomedicine.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12672-025-03603-y.

Introduction

Primary Liver cancer is among the six most prevalent cancers globally and ranks as the third leading cause of cancer-related mortality worldwide in 2020. Hepatocellular carcinoma (HCC) constitutes the predominant form of Liver cancer, representing 75–85% of all primary liver cancers [1]. Hepatitis B virus (HBV) infection emerges as the most significant etiological factor in HCC development, accounting for approximately 50% of all cases [2]. Other notable risk factors encompass hepatitis C virus (HCV) infection, chronic alcohol abuse, diabetes, and obesity-related nonalcoholic steatohepatitis [3]. The diagnosis of HCC predominantly relies on imaging studies and hematologic tumor markers, with liver ultrasound and serum alpha-fetoprotein being the most frequently utilized surveillance methods [4]. Clinical guidelines recommend biannual screening for high-risk individuals [5]. The Barcelona Clinic Liver Cancer (BCLC) staging system serves as the universal staging framework for HCC [6]. Early-stage HCC (BCLC stage 0/A) can be managed with surgical resection and radiofrequency ablation, although recurrence rates are as high as 70% [7, 8]. Transcatheter arterial chemoembolization is the preferred treatment modality for intermediate-stage HCC [6]. However, due to the absence of tumor-specific symptoms, the majority of HCC cases are diagnosed at an advanced stage [9]. Prior research has demonstrated that tumor heterogeneity (ITH) is a critical prognostic factor in malignant tumors, contributing not only to tumor progression but also to drug resistance [10]. HCC, characterized by its high heterogeneity with diverse genetic or epigenetic alterations [11–13], carries a poor prognosis, with a 5-year survival rate of merely 10% [14]. Molecularly targeted agents and immunotherapies currently form the cornerstone of treatment for advanced HCC. Sorafenib, the first and only molecularly targeted drug approved by the FDA for systemic therapy of advanced HCC, inhibits tumor proliferation and angiogenesis by targeting RAF signaling as well as vascular endothelial growth factor, platelet-derived growth factor, and KIT [15], thereby improving patient survival by approximately 7–10 months [16]. However, sorafenib’s antitumor efficacy is significantly constrained by issues such as drug toxicity, hydrophobicity, bioavailability, and drug resistance. Consequently, numerous scientists are endeavoring to develop novel therapeutics that enhance drug bioavailability, mitigate side effects, and optimize the overall tumor prognosis. Recent evidence indicates that nano-formulated herbal compounds, such as curcumin-encapsulated liposomes, exhibit synergistic anti-HCC activity both in vitro and in orthotopic mouse models [17].

Nanotechnology, an emerging field with varying definitions across nations, is unified by the application of nanoscale (1–100 nm) structures [18]. Nanotechnology employs nanocarriers to encapsulate hydrophobic small molecule drugs and nucleic acids, facilitating intracellular drug delivery and reducing drug excretion rates and toxicity through enhanced biodistribution and pharmacokinetics, thereby improving drug bioavailability [19, 20]. Nanoparticles (NPs) exploit the leaky endothelial tissue surrounding tumors to extravasate and accumulate in tumor cells via the enhanced permeability and retention (EPR) effect [21], constituting the primary mechanism for the majority of nanomedicines currently on the market in treating tumors. Receptor-mediated endocytosis represents another pathway for targeted drug delivery; nano-formulations augment intracellular drug accumulation by recognizing specific tumor cell receptors and selectively releasing encapsulated cytotoxic drugs to tumor cells [22, 23]. Additionally, certain NPs, such as liposomes, can utilize their thermosensitive properties for targeted drug delivery by inducing local hyperthermia and triggering conformational changes in thermosensitive nanoparticles to specifically release cytotoxic drugs at the heated tumor site, while minimizing damage to adjacent normal tissues [24, 25]. A Phase 3 clinical trial has demonstrated that ThermoDox, a heat-sensitive liposomal doxorubicin, is efficacious in treating unresectable HCC in combination with radiofrequency ablation (RFA) and significantly diminishes the severity of adverse effects [26]. Following extensive exploration and research, the current nanotechnology-based targeted drug delivery systems have yielded promising results. Nanomedicines including Doxil (liposomal doxorubicin), Onivyde (liposomal irinotecan), Abraxane (albumin-bound paclitaxel), and Vyxeos (liposomal cytarabine and daunorubicin) have received FDA approval and are utilized in antineoplastic therapy [27–30]. Beyond therapeutic applications, nanotechnology also holds significant potential in the early detection and diagnosis of tumors [31]. Studies reveal that the early detection success rate for the most commonly employed Liver ultrasound examinations stands at merely 47% [32]. Early diagnosis is crucial for improving the grim prognosis associated with HCC. The long-term stability of nanomaterials facilitates the design of more sensitive bioassays for the detection of tumor biomarkers [33]. In 1999, Makarova achieved ultrasensitive target detection using nanoparticles composed of silica and fluorescent dyes, a technology proven useful for detecting tumor antigen markers and providing early assistance in tumor testing [34]. Furthermore, the combination of NP-based optical contrast agents with modern optical imaging techniques can enhance the resolution of in-vivo tumor imaging [35]. Mulan Li discovered that thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION) exhibit superior relaxation rates (R2 values) and enhanced MR contrast effects in HCC tissues of nude mice, as demonstrated in a comparison study, and can be employed for HCC treatment and early monitoring [36].

Nanotechnology serves as a potent tool for drug delivery and targeting in HCC, although the majority of research in this domain remains in the animal testing phase [37–39]. This underscores the research potential of nano-targeted HCC treatments, warranting further analysis and investigation. Bibliometric methods, leveraging various statistical analysis software and techniques, are vital research tools for visually presenting the research achievements and future trends within specific journals and disciplines [40, 41]. This study aims to employ a bibliometric approach to visually analyze the application of nanotechnology in HCC, synthesizing the current developmental landscape and future research directions and hotspots, with a particular emphasis on an overview of nanotargeted therapies for HCC.

Materials and methods

Retrieval strategy

In October 2022, we searched the WOS core database for publications dated from January 1, 2012 to October 31, 2022. The retrieval strategy was: (TS=(hepatoma*)OR TS=(HCC)OR TS=(liver carcinoma)OR TS=(hepatic cancer) OR TS=(hepatocarcinoma)OR TS=(hepatic carcinoma)OR TS=(hepatocarcinoma)OR TS=(hepatic carcinoma)OR(TS=(hepatic carcinoma)OR TS=(liver cancer)OR TS=(Hepatocellular carcinoma))AND (TS=(nanotechnology) OR TS=(nano-medicine) OR TS=(nanomedicine) OR TS=(nanomedical) OR TS=(nanoparticles) OR TS=(nanoparticle) OR TS=(nanometer particle) OR TS=(nanomaterials)).

The inclusion criteria for the contribution are as follows: (1) the theme is HCC and nanotechnology research; (2) Literature types include monographs and reviews and freely available data; 3) The language of the literature is English.

The exclusion criteria are as follows: (1) the article is not relevant to the research topic; (2) The article is a conference summary, news or briefings.

To ensure the quality of the search, two review assessed the complete literature and invited a third reviewer to co-analyse the divergent literature until an agreement is reached. Figure 1 shows a flowchart of the document selection process. Figure 2 is a graphical abstract of this article.

Fig. 1.

Flowchart of literature selection

Fig. 2.

Graphical abstract

Analytical methods

The literature that met the study criteria was imported into the system and visualized by using CiteSpace and R software to analyze fields such as author, country, affiliation, journal, keywords, references, etc. CiteSpace (http://cluster.cis.drexel.edu/~cchen/citespace/download/) was used to detect and visualize current scientific knowledge, detect current research trends in the field and determine future research directions [42, 43]. The bibliometrix R package, an Open source software, was used to perform quantitative and qualitative analysis of research results [44]. H-index (Hirsch Index): Defined as the maximum value of h such that at least h papers have been cited at least h times each. This metric measures sustained academic impact through dual thresholds (paper quantity and citation frequency). G-index (Egghe Index): An extension of the H-index, where g is defined as the maximum value such that the cumulative citations of the top g papers are ≥ g². This metric emphasizes the concentration of highly cited papers. M-index (Mean Citation Index): Calculated as the ratio of total citations to the number of papers, reflecting average research activity. This indicator identifies emerging research hotspots.

Statistical analysis

SPSS (IBM SPSS Statistics 27) was used for statistical processing of the data. P < 0.05 indicates a statistically significant difference in.

Results

From 2012 to October 2022,W0S found a total of 4,953,544 articles that met the exclusion criteria were excluded, and then 37 were screened using the R language pack Duplicate Literature was further excluded and a total of 4,372 articles were included in the analysis, including 3,934 monographs and 438 reviews.

Publishing trends

Publication volume serves as a pivotal metric for gauging trends within scientific research. The line chart depicted in Fig. 3 illustrates the annual publication count from 2012 through October 2022, revealing several trends. Between 2012 and 2018, there was a consistent escalation in scholarly interest regarding nanotechnology in hepatocellular carcinoma (HCC), culminating in 2018 with the annual publication count reaching 500. The period from 2018 to 2020 witnessed a stabilization, with the annual publication numbers hovering around the 500 mark, indicating a plateau in research output. However, from 2020 to 2021, there was a marked acceleration in publication rates, surpassing all previous records in 2021 with a total of 597 articles. This figure represents the zenith of research activity in HCC nanotechnology over the past decade, signifying 2021 as the most prolific year in this field of study.

Fig. 3.

Annual publication volume on nanotechnology in hepatocellular carcinoma research

Countries and institutions of publications

Over the past decade, a total of 64 countries have contributed to the Literature on HCC nanotechnology research. China stands out with the highest research output, boasting 2,473 publications, which accounts for 55.6% of the total and secures its position at the forefront of the publication rankings(Fig. 4A). China’s total citations in nanomedicine HCC research reached 72,082, with both the H-index (101) and G-index (143) significantly higher than those of other countries (e.g., the United States H-index 87, India 50). This indicates that China not only leads in the quantity of papers but also demonstrates advantages in research quality and sustained influence. The M-index (9.182) further reflects China’s research activity far surpassing other countries (e.g., the United States 7.909, India 4.545)(Supplementary Table 1). This substantial contribution underscores the extensive engagement of Chinese researchers in this field, far exceeding that of other nations.

Fig. 4.

A Country of the corresponding author of the relevant publication; B Country Collaboration Map, The co-authorship map provides a visual representation of collaborative networks, where nodes represent individual authors. A line connecting two nodes signifies that the corresponding authors have co-authored at least one publication. The thickness of the nodes and the intensity of the map’s color coding are indicative of the authors’ publication counts, reflecting the extent of their scholarly contributions to the field. C Publication trends of the top 10 institutions

The prevailing trend in publication is the Single Country Publication (SCP), as depicted in Fig. 4A. Among the current body of literature, researchers from China, the USA, India, Egypt, and Saudi Arabia are notably involved in multinational collaborative efforts. Notably, China and the United States exhibit the most extensive cooperation in this regard, as illustrated in Fig. 4B.

Between 2012 and October 2022, a total of 3,655 institutions have published papers on nanotechnology in hepatocellular carcinoma (HCC). Sun Yat-sen University leads with the most prolific output, having published 218 papers, followed closely by Zhejiang University with 215 papers, and Jilin University with 153 papers. Sun Yat-sen University has a total citation count of 4,625 (H-index 38), ranking third in total citations but tying with Nanjing University (H-index 38) for second place, indicating balanced research Quality and influence. Zhejiang University leads with a total citation count of 5,510 and H-index 41. Its G-index (64) demonstrates outstanding contributions to highly cited papers, further validating the research depth of Chinese institutions. The top ten institutions, all of which are universities, and nine of which are based in China, account for 35% (1,538) of the total publications (Supplementary Table 2). This distribution underscores China’s leading role in nanotechnology research for HCC. From 2012 to 2020, the academic output of each institution exhibited an overall upward trend, with relatively minor variations. However, in 2020, Sun Yat-sen University and Zhejiang University’s academic contributions to HCC nanotechnology research significantly outpaced other institutions, demonstrating a heightened interest and engagement in this field (Fig. 4C).

Publication of journals

The INTERNATIONAL JOURNAL OF NANOMEDICINE has been the most prolific publisher of nanotechnology research on Liver cancer over the past decade, with a total of 190 articles published. Although its annual publication count was slightly lower than BIOMATERIALS in 2012 and RSC ADVANCES in 2015, it led other journals in all other years (Fig. 5A). Additionally, the INTERNATIONAL JOURNAL OF NANOMEDICINE was the most cited journal, amassing 5,644 citations (Supplementary Table 3), followed by BIOMATERIALS (5,241 citations), ACS APPLIED MATERIALS & INTERFACES (3,491 citations), JOURNAL OF CONTROLLED RELEASE (3,367 citations), and ACS NANO (2,473 citations).

Fig. 5.

A Top 10 journals of related publications; B Double map overlay of related publications journal, The double map overlay of journals illustrates the thematic distribution of interdisciplinary research, with cited journals on the left and citing journals on the right. The size of the ellipses is positively correlated with the number of authors and publications, while the color of the links distinguishes the disciplinary attributes of the journals

H-index, g-index, and m-index are used to analyze the most influential journals. A deeper analysis of the journals’ H-index, g-index, and m-index reveals that BIOMATERIALS has an outstanding performance, not only in citations but also in these indices, indicating its recognition among researchers in the field. The remaining four journals with significant influence are the INTERNATIONAL JOURNAL OF NANOMEDICINE, ACS APPLIED MATERIALS & INTERFACES, JOURNAL OF CONTROLLED RELEASE, and ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY.

The double map overlay of journals illustrates the thematic distribution of interdisciplinary research, with cited journals on the left and citing journals on the right. The size of the ellipses is positively correlated with the number of authors and publications, while the color of the links distinguishes the disciplinary attributes of the journals. There are four citation paths: the yellow path indicates frequent citations of literature published in molecular/biology/immunology journals in molecular/biology/genetics and chemistry/materials/physics journals; the purple path shows that literature published in physics/materials/chemistry journals is frequently cited in molecular/biology/genetics and earth/genetics journals. The purple path also indicates that literature published in physics, materials, chemistry journals is often cited in molecular/biology/genetics journals, earth/geology/geophysics journals, and chemistry/materials/physics journals (Fig. 5B).

Most cited literature

Japanese scholar Hiroshi Maeda’s article, “Macromolecular therapeutics in cancer treatment: The EPR effect and beyond,” published in the Journal of Controlled Release, became the most cited article in the Web of Science (WOS) with 604 citations. This literature primarily discusses various issues related to the targeting of cancer drugs associated with EPR (Enhanced Permeability and Retention) effects, including a brief introduction to EPR effects, their definitions, involved factors, heterogeneity, and various methods of enhancing EPR effects [45]. Passive targeting based on enhanced permeability and EPR effects is the mechanism upon which most clinical nanomedicines are currently targeted against tumors, which may account for the high number of citations for this literature. Following are Qin Wei’s article, “Biocompatible Nanoparticles with Aggregation-Induced Emission Characteristics as Far-Red/Near-Infrared Fluorescent Bioprobes for in-vitro and in-vivo Imaging Applications [46], ” and Seabra Amedea B’s publication, “Nanotoxicity of graphene and graphene oxide [47]. ” Both articles were recognized by other researchers and received up to 500 citations (Fig. 6A).

Fig. 6.

A Top 20 most cited publications in HCC nanotechnology research; B Publication historical direct citation network

Breaking down the literature by year, the nodes in Fig. 6B represent the most cited documents, and the lines connecting them indicate that the papers were cited in the same article. The analysis of the internal citation network revealed that mezghrani (2015) and Zhang (2016) and cai ye (2016) were the obvious nodes. The article “Mezghrani (2015)” focuses on the study of nanoparticle-targeted therapy for HCC [48]. Zhang X’s article “Drug delivery system targeting advanced hepatocellular carcinoma: Current and future” focuses on the biology and physicochemical properties of HCC and Recent research on HCC by drug delivery systems and future research trends [49], the article “cai (2016)” provides an overview of a novel nanoparticle drug delivery system modified with glycyrrhetinic acid, focusing on the efficacy of the treatment of HCC and its mechanisms [50]. The three articles all focus on “HCC”,” nanoparticles” and “drug delivery”, which are hot keywords in nanotechnology research in HCC, therefore their articles collect a large number of literatures in this knowledge field.

Most cited authors in published products

From 2012 to October 2022, a total of 16,631 authors published papers related to HCC and nanotechnology. Supplementary Table 4 shows the top 10 authors in terms of publication volume. Notably, WANG Y, Zhang Y, Liu Y, and Li J all have more than 60 academic articles, with Wang Y leading with 88 articles. The Sankey diagram can represent the relationship between authors, journals, and keywords. The leftmost column shows the journal name, the middle column shows the author’s name, and the rightmost column represents common keywords. The size of the rectangle and the thickness of the lines are proportional to the number of publications. Figure 7 shows that WANG Y, ZHANG Y, and LIU Y, the most productive authors, frequently used “HCC,” “nanoparticles,” “drug delivery,” and “doxorubicin” as keywords in their literature.

Fig. 7.

Three-field plot, also known as the Sankey diagram, can depict the relationship among authors, journals, and keywords. The leftmost column displays the names of journals, the middle column shows the names of authors, and the rightmost column represents common keywords. The size of the rectangles and the thickness of the lines are directly proportional to the number of publications

Analysis of hot topics and themes of nanotechnology research in HCC

Keywords are words that represent the central content of the literature, and their analysis can help quickly identify the themes and concerns of a particular field. Keywords were analyzed using visual word clouds and heatmaps through the R language. The “word cloud” is a visual representation of word frequency, where the size of the word cloud represents the frequency of keywords [51] (Fig. 8A). Heatmaps can simply aggregate large amounts of data and use a progressive color band to visualize spatial data sparsity and trends (Fig. 8B). The top 10 hot keywords in the analysis are NANOPARTICLES (n = 1,314, 11%), HEPATOCELLULAR-CARCINOMA (n = 979, 8%), DRUG-DELIVERY (n = 703, 6%), in-vitro (n = 610, 5%), DELIVERY (n = 578, 5%), CANCER (n = 563, 5%), CELLS (n = 462, 4%), THERAPY (n = 435, 4%), APOPTOSIS (n = 361, 3%), and DOXORUBICIN (n = 322, 3%) (Supplementary Table 5).

Fig. 8.

A Keyword cloud, The Keyword cloud visually represents the frequency of keywords, with the size of each word indicating its occurrence frequency in the literature. B Keyword heatmap

Bursts of keywords

Burst Keywords Analysis helps identify areas of particular concern to the relevant scientific community and often indicates a major turning point in research during a given period [52]. From Fig. 9, “gene delivery,” “DNA,” and “particles” were the first keywords to appear, and after 2016, scientific research gradually shifted its focus to “nanoparticles,” “HCC,” “drug delivery,” “in-vivo,” and “in-vitro” directions. From 2016 to 2021, “nanoparticles” were the hottest area of research. The sudden explosion or proliferation of keywords has been noted as an indicator of “potential frontiers.” The new hot keywords “sorafenib” and “antioxidant” in 2019 are currently not as concerned as “nanoparticles” and “drug delivery,” but they may represent the focus of subsequent research.

Fig. 9.

Keyword trend graph, bubble size is proportional to the frequency of keyword repetition

Theme map

Theme maps can be used to analyze trends and knowledge structures because they provide information about the current state of development, drivers, and potential of word clustering in research areas [53]. In this plot, the x-axis represents centrality, which is the strength of the association of one clustered word with other clustered words, and the distance on the x-axis represents the level of importance. The y-axis represents density, that is, the strength of the association of words in the cluster, and the density represents the level of development [54]. Each cluster is generated from a set of words with similar occurrences and relevances, so the frequency of word repetition affects the size of the cluster [54]. Each quadrant of the theme map represents a different theme. Figure 10 shows the four clusters identified in a two-dimensional space. Nanoparticles, delivery, and cancer in the first quadrant belong to “motor themes” and are closely related to all topics, indicating their high importance and development in the field of research. Apoptosis, toxicity, and cytotoxicity in the second quadrant are “Niche Themes,” which means that the three themes are closely connected internally, highly developed within each other, but less connected to other themes, well developed, and not important to the current field. The third quadrant of DNA, diagnosis, quantum dots belongs to marginal subjects and is identified as an “emerging or declining theme,” indicating that there is neither good development nor too much importance and may belong to emerging or declining fields. Located in the fourth quadrant are hepatocellular-carcinoma, drug-delivery, and in-vitro’s clusters, which are closely related to other external clusters and are important to the field but not internally related enough, and they are still in the development stage and belong to “Basic Themes,” indicating that this section is a promising area in HCC and nanotechnology.

Fig. 10.

Strategic diagram of research themes. Quadrants: Q1 (Motor Themes), Q2 (Niche Themes), Q3 (Emerging/Declining), Q4 (Basic Themes)

Structural analysis of theme

Multiple Correspondence Analysis (MCA) is an exploratory multivariate technique for graphical and numerical relationship analysis of multivariate categorical data [55]. MCA was performed using the conceptual Structure function in the bibliometrix R-package to map the conceptual structure of the fields, and the closer the keywords are in the map, the more similar they are in terms of distribution. From Fig. 11, it can be concluded that the best reduction achieved in the first two dimensions of MCA accounts for about 65.81% of the total variability. Violet clusters are associated with nanoparticles, including “old nanoparticles,” “magnetic nanoparticles,” “iron oxide nanoparticles,” and “mesoporous silica nanoparticles.” Green clusters are mainly related to cytotoxicity, including keywords like “toxicity,” “cytotoxicity,” and “cellular uptake.” The red cluster deals with the mechanisms that nanotechnology applies to HCC, including “apoptosis,” “expression,” and “inhibition” among other keywords. The blue cluster refers to current anti-tumor research such as “breast cancer,” “HCC,” and “doxorubicin,” as well as “polymeric micelles” and other keywords. The analysis of the structural map reveals the depth and breadth of the current research field.

Fig. 11.

Conceptual structure map from Multiple Correspondence Analysis. Keyword proximity indicates similarity

Discussion

General information

This paper evaluates the research trends in the Literature concerning nanotechnology in HCC from 2012 to October 2022. The study’s outcomes indicate a general upward trend in publications on this subject, suggesting a continued enthusiasm for the application of nanotechnology in HCC research over recent years. However, the overall growth trend from 2018 to 2020 is less pronounced compared to previous periods. After 2020, there is a noticeable increase in scholarly interest, with the growth rate surpassing historical levels. Over the past decade, 64 countries have contributed to the Literature on HCC and nanotechnology, with China leading significantly ahead of the United States, India, Egypt, and South Korea, Likely due to its high HCC prevalence, accounting for 55% of all global HCC cases [56]. The analysis shows that independent publishing within individual countries remains the current mainstream trend, with China maintaining its leading position in co-publishing with other nations, particularly the United States, India, Egypt, and South Korea, with the majority of collaborations occurring between China and the United States.

The International Journal of Nanomedicine is the journal with the largest collection of nanotechnology-related HCC research. Established in 2006 and published in New Zealand, this Quarterly journal covers a wide range of topics, including nanodrug delivery, biosensors, regenerative nanomedicine, nanodiagnostics, nanoinformatics, nanotoxicity, and all aspects of nanotechnology applications across the biomedical field. The journal currently boasts an impact factor of 7.033. Meanwhile, Biomaterials is recognized as the journal with the strongest overall impact, focusing primarily on “biomaterials,” with an impact factor of 15.304 in 2022. By analyzing the number of articles published, citations, and other data, researchers can more effectively select appropriate journals for publishing academic achievements. Through the analysis of keywords, we concluded that the main research focus in HCC nanotechnology over the past decade has been the application of nanoparticles in anti-tumor therapy, particularly through drug delivery. The MCA algorithm constructs a distribution field of keywords, and the results indicate that the research on novel nanoparticles, “nanoparticle anti-tumor therapeutic mechanisms,” “encapsulated cytotoxic drugs,” and nanoparticle auto-toxicity are currently the four major areas of focus. Among these, the research on assembling nanoparticles with commonly used cytotoxic drugs, such as sorafenib and doxorubicin, represents an area with significant development potential.

Targeted therapy with nanotechnology

Nanotechnology-based targeted drug delivery systems (NTDDS) have demonstrated potential as a promising therapeutic approach for hepatocellular carcinoma (HCC) [57]. Nanoparticles (NPs) serve a dual role in cancer treatment: they facilitate the transportation of anti-neoplastic agents and enable specific recognition of certain receptors on malignant cells, thereby directing the release of drugs to targeted tumor tissues. Moreover, certain polymeric materials integrated into NPs possess inherent cytotoxic properties, synergizing with encapsulated drugs to enhance anti-tumor efficacy [57].

Based on material properties, NPs are categorized into inorganic and organic entities. Inorganic NPs encompass iron oxide, gold nanoparticles, quantum dots, and silicon dioxide NPs, among others. Organic NPs primarily consist of liposomes, polymeric nanoparticles, micelles, dendrimers, and polymers [57]. Among these, liposomes and polymeric nanoparticles have emerged as the most frequently utilized NPs in contemporary applications [58, 59].

Liposomes are recognized for their non-toxicity and biocompatibility, enhancing the solubility of hydrophobic drugs and boasting high drug loading efficiency. They can be combined with both hydrophilic and lipophilic drugs, thereby augmenting therapeutic efficacy. Liposomes provide stability, are facile to synthesize, and mitigate the toxicity of the encapsulated drugs [60–62]. They represent the first class of therapeutic NPs to gain approval for cancer treatment [63].

Polymeric nanoparticles are deemed ideal drug carriers due to their biodegradability, water solubility, biocompatibility, biomimetic properties, and storage stability. They also feature numerous active functional groups on their surface, which can be conjugated with surface ligands [64]. These attributes have led to their widespread application in clinical practice.

Passive targeting

The neovascularization that occurs within the context of malignant tumor cells often manifests as leaky vasculature, characterized by aberrant branching and endothelial gaps with pore diameters typically ranging from 100 nm to 2 μm [65]. Particulate matter can exploit these interendothelial spaces, allowing for translocation from peripheral vessels to the tumor site. Moreover, the lymphatic drainage within the tumor vasculature is often compromised, and both of these factors can lead to the accumulation of particulate matter at the tumor site—a phenomenon known as the Enhanced Permeability and Retention (EPR) effect [65]. Nano-passive targeting leverages the EPR effect to accumulate nanoparticles, which are smaller than the pore size, in specific tumor tissues [66]. The EPR effect is influenced by the size, geometry, and surface charge of the nanoparticles. Augmenting the EPR effect can potentially increase drug delivery efficiency by 2–3 fold [67]. However, the reticuloendothelial system present in the liver and spleen can diminish the EPR effect, thereby reducing the delivery rate of nanoparticles to hepatocytes [65]. Polyethylene glycols (PEGs) are macromolecules widely incorporated into passively targeted nanosystems to extend blood circulation times and enhance drug efficacy [68]. The use of PEG is based on its high solubility, biocompatibility, and favorable tolerance in aqueous environments; PEG-modified nanoparticles can achieve a near-zero zeta potential, thereby avoiding recognition by the immune system and subsequent uptake by the mononuclear phagocyte system [69–71]. Abnormal vascular structures have been identified as the foundation of passively targeted pathophysiology [72]. Neovascularization is particularly abundant in HCC, and Kaminskas et al. demonstrated in 2011 that the use of PEGylated dendrimers and PEGylated liposomes can enhance liver tumor regression through the EPR effect in mouse HCC cells [73]. Although many passively targeted drugs have reached the clinical trial stage, passive targeting is a highly heterogeneous phenomenon, exhibiting significant variability between different tumors and among patients [74]. Consequently, researchers have increasingly turned their focus to another domain of nanotargeted therapy—active targeting.

Active targeting

Active targeting, also known as ligand-mediated targeting, involves the induction of conformational changes in target cells by binding to specific complementary receptors on these cells [75]. Active targeting represents the primary direction of development in nano-targeted therapy. Hepatocellular carcinoma (HCC) cell membranes overexpress a variety of receptors, with common targets for active targeting therapy including the Asialoglycoprotein receptor (ASGP-R), Glypican-3 (GPC3), Glycyrrhetinic acid receptor, Transferrin receptor (TFR), and Folate receptor (FR).

ASGP-R, a transmembrane protein also known as the galactose receptor or hepatic lectin, is predominantly expressed on hepatocytes and is rarely found on extrahepatic cells, making it an ideal receptor for liver-targeted therapies. It recognizes a variety of ligands containing terminal galactose (Gal) or N-acetylgalactosamine (GalNAc) residues [76]. ASGP-R expression is low on poorly differentiated HCC tissues and high on well-differentiated HCC tissues [77], indicating its potential as an early HCC detection marker. Bon and colleagues developed a mouse target-mediated drug disposition model that investigates the exceptional transport capacity of ASGPR to deliver drugs from the bloodstream to the liver after binding to nanocarriers with specific ligands [78]. Nair synthesized a novel nanoparticle formulation by conjugating gemcitabine with polymeric carriers and galactosylated chitosan, demonstrating the hepatic targeting of gemcitabine-loaded galactosylated chitosan nanoparticles and their superior antitumor effects compared to the free drug in terms of accumulation percentage and organ distribution [79].

GPC3, a carcinofeto-proteoglycan located on cell membranes, is closely associated with HCC occurrence and poor prognosis due to its role in regulating growth factor activity [80, 81]. GPC3 is overexpressed in approximately 81% of HCC tissues and serves as a specific receptor for HCC [82, 83]. Its expression is linked to poor prognosis after surgical resection, early HCC recurrence, and an increased risk of death in HCC patients, making it an independent prognostic factor for poor disease-free survival in early HCC patients [84, 85]. Huaiyong Gan et al. demonstrated that sorafenib-loaded polymeric nanoparticles coupled with anti-GPC3 antibody formed composite nanoparticles with significantly higher cellular uptake in hepatocytes than non-targeted NPs, and these composite nanoparticles exhibited greater cytotoxicity than non-targeted NP-SFB and free SFB without significant side effects. Additionally, the results showed that NP-SFB-Ab had a substantial inhibitory effect on tumor tissue growth [86]. Wnt protein binds to the core protein of GPC3 or heparan sulfate glycan chains, acting as a ligand for GPC3 [57]. The Wnt pathway promotes cell proliferation by inducing nuclear transcription and accumulation of β-catenin in the cytoplasm [87, 88].

The Glycyrrhetinic acid receptor (GA-R) is another receptor abundantly present on Hepatocyte membranes. Previous studies have found that GA-R expression in tumor tissue is 1.5 to 5 times that of normal tissue [89]. Glycyrrhetinic acid is its ligand and has been widely used in the treatment of liver diseases. To further investigate the role of GA as a hepatocyte-targeting ligand, several GA-modified nanoparticles have been clinically developed, including chitosan/poly(ethylene glycol)-glycyrrhetinic acid nanoparticles [90], GA-modified poly(ethylene glycol)-b-poly(γ-benzyl L-glutamate) micelles [91], GA-modified liposomes [92], GA-PEG cationic liposomes [93], and GA-Oxaliplatin-liposomes [94]. Researchers have loaded cytotoxic drugs onto GA-modified nanoparticles and confirmed their excellent liver targeting effect through animal experiments. The Transferrin receptor (TFR) is a homodimeric transmembrane glycoprotein overexpressed on various malignant cells [95–97]. TFR-2 is strongly expressed in early-stage HCC with indistinct tumor borders and well-differentiated histology, while TFR-1 is highly expressed on the cell membrane of advanced HCC with macroscopic vascular invasion in both cancerous and non-cancerous tissues [98]. Transferrin (TF) is a natural ligand of TFR. Current research on TF-modified nanoparticles has been conducted across various malignancies, with Fred C. Lam et al. demonstrating that targeted TF-modified nanoparticles can enhance the efficacy of the combination of temozolomide and bromodomain inhibitors in the treatment of gliomas [99]. Andrew J. Clark and Mark E. Davis found that adding an acid-dissociable link between transferrin and the nanoparticle core increased the uptake of targeted nanoparticles by the brain [100]. An oxaliplatin-loaded TF lipid formulation is being investigated for the treatment of metastatic gastric, gastroesophageal junction, and esophageal adenocarcinoma and is currently in phase II clinical trials [101]. Yaohua Wei used Tf-Ps-Dox, a combination of TF with polymeric adriamycin, as a potent tool for targeted chemotherapy in HCC mice [102].

The Folate receptor (FR) is a tumor-associated antigen that binds to folic acid (FA) and mediates endocytosis through high-affinity coupling [60]. FR is overexpressed in many cancer cells, and FA is the natural ligand of FR. Previous studies have found that FA is not only non-immunogenic but also easily modified [103]. For these reasons, FA-modified nanoparticles are widely believed to be useful in targeted therapy for malignant tumors. For these reasons, FA-modified nanoparticles are widely believed to be useful in targeted therapy for malignant tumors. Studies such as folic acid-coupled paclitaxel liposomes against drug resistance in ovarian cancer cells [104], Docetaxel-lipid-based-nanosuspension for antitumor therapy [105], and the use of folic acid as a homing device for targeting tumors [106] demonstrate the role of FA-modified nanoparticles in targeted tumor therapy.

Future perspectives on nanotechnology in the management of hepatocellular carcinoma

The application of nanotechnology in medicine represents a primary area of development within this rapidly evolving field. Since its introduction in 1974, nanotechnology has made significant contributions to oncology, offering innovative approaches for the early detection, diagnosis, and treatment of tumors [107]. In exploring the application trends of nanomedicine in the treatment of hepatocellular carcinoma (HCC), it is essential to acknowledge the remarkable advancements achieved in this field and its revolutionary potential in cancer therapy. Nanomedicine provides new strategies for HCC treatment by facilitating targeted drug delivery systems, improving drug biodistribution and pharmacokinetics, reducing systemic toxicity, and enhancing local drug concentrations within tumor tissues. Both active and passive targeting mechanisms, which differentiate between normal and tumor pathological tissues while selectively eliminating malignant cells, are considered core areas of nanotechnology [108]. Current research trends indicate a shift in the application of nanomedicine in HCC treatment from basic research to clinical translation. For instance, through receptor-mediated endocytosis, nanocarriers can enhance the accumulation of drugs within tumor cells by recognizing specific receptors on the surface of these cells and selectively releasing encapsulated cytotoxic agents. Additionally, certain nanoparticles, such as thermosensitive liposomes, can release cytotoxic drugs specifically at heated tumor sites by inducing conformational changes, thereby limiting damage to surrounding healthy tissues. This thermosensitive drug delivery system has demonstrated promising efficacy and reduced side effects in clinical trials, providing new options for HCC treatment.

However, the application of nanomedicine in HCC therapy also faces challenges. First, the biocompatibility and long-term toxicity of nanoparticles remain critical areas requiring further investigation. Although many nanoparticles have shown efficacy in-vitro and in animal models, their long-term effects and safety in humans must be validated through large-scale clinical trials, particularly regarding their impact on biological systems and the immune response [109]. While preclinical studies using HepG2 and C3A cell lines have revealed dose-dependent hepatotoxicity for gold, silver, and iron oxide nanomaterials [110], and a 180-day rat study demonstrated elevated fibrosis markers after PEGylated iron oxide exposure, most animal experiments still rely on ≤ 90-day follow-up periods [111]. This discrepancy is particularly concerning given that gold nanoparticles exhibit prolonged retention (> 12 weeks) in murine livers, highlighting the urgent need for chronic toxicity models. Notably, the integration of machine learning with traditional Chinese medicine, as demonstrated in Xiao-Chai-Hu decoction (XCHD) research for liver disease trilogy management, offers complementary insights for optimizing nanotechnology-based precision medicine strategies in HCC [112]. Besides, the research and development of Chen et al. in a GMP-compliant non-animal platform for the cultivation of functional hepatocytes from human hepatoblast cells (hGBECs) provides a key resource for evaluating nanoparticle drug delivery systems in hepatocellular carcinoma models, particularly for evaluating drug metabolism and hepatotoxicity on a clinical-grade cell platform [113]. Second, Lack of Cirrhosis-Specific Toxicological Models, Over 80% of HCC patients have underlying cirrhosis, where impaired Kupffer cell function, portosystemic shunting, and coagulopathy may amplify nanocarrier off-target effects. However, only 4% (7/173) of in vivo studies utilize cirrhotic animal models, and none systematically evaluate cirrhosis-specific endpoints (e.g., portal hypertension, coagulation parameters) [114, 115]. Among Phase II nanodrugs (e.g., ThermoDox^®, MTL-CEBPA), neither has disclosed toxicokinetic data in cirrhotic populations, despite over 80% of HCC patients presenting with Child-Pugh B/C status at diagnosis. Regulatory gaps persist, as evidenced by the 2023 FDA draft guidance failing to provide dose adjustment recommendations for liver dysfunction patients—a critical omission given the altered pharmacokinetics of nanomaterials in cirrhotic individuals [116]. Furthermore, Inadequate Monitoring of Immune-Related Adverse Events: Preclinical evaluations of nanomedicines in HCC predominantly prioritize efficacy metrics such as tumor inhibition rates and survival benefits, while systematically neglecting critical immune-related toxicity assessments. Animal studies rarely incorporate quantitative evaluation of long-term nanoparticle accumulation in vital organs (liver, kidney, lung), fibrogenic potential (e.g., TGF-β/collagen pathway activation), or immunotoxicity parameters including cytokine storms and lymphopenia [117]. This oversight extends to emerging combinatorial strategies, such as PD-1 antibody-conjugated platelet membrane nanoparticles loaded with sorafenib, which demonstrate enhanced antitumor efficacy in animal models but lack standardized protocols for assessing immune microenvironment perturbations [118]. Clinical trials similarly omit prospective surveillance of immune organ damage, creating a translational gap in predicting and mitigating immunotherapy-associated adverse events.

Furthermore, enhancing the targeting specificity of nanoparticles to tumor tissues while minimizing damage to normal tissues is a pressing issue within the field of nanomedicine. Beyond physical targeting challenges, metabolic interactions mediated by drug-metabolizing enzymes also warrant attention. Recent studies revealed that oridonin, a diterpenoid from Rabdosia rubescens, induces CYP2c/3a enzymes via PXR activation in humanized models [119]. This metabolic modulation effect suggests potential drug-drug interaction risks when combining natural compounds with nanotherapeutics, highlighting the need to evaluate cytochrome P450 enzyme induction in nanoparticle-based HCC therapies.

Looking ahead, research directions for nanomedicine in HCC treatment may focus on several key areas: First, the development of novel nanomaterials to improve drug loading efficiency and stability while reducing toxicity to normal tissues; second, the optimization of nanoparticle surface modifications to enhance targeting and penetration capabilities for precise tumor targeting; third, the exploration of combinatorial approaches involving nanoparticles and existing treatment modalities (such as surgery, radiotherapy, and chemotherapy) to improve therapeutic outcomes and patient survival rates; and finally, the strengthening of clinical trials for nanoparticles to validate their safety and efficacy, thereby facilitating their application in HCC treatment.

Limitations

This study’s literature search was confined to the Web of Science (WoS) database, and the retrieved articles were limited to those published in English, which may have introduced a degree of linguistic bias. Additionally, the scope of the literature types was restricted: the research primarily focused on peer-reviewed journal articles, potentially overlooking other forms of academic output such as conference papers, patents, and book chapters.

Conclusion

In this study, we conducted a thorough analysis of the literature on the application of nanomedicine in hepatocellular carcinoma (HCC) treatment spanning, elucidating the research trends and advancements within this domain. Our analysis reveals that nanomedicine possesses significant potential in enhancing early detection rates for HCC, optimizing drug utilization efficiency, and improving patient prognoses, with a particular emphasis on the encapsulation of cytotoxic drugs within nanoparticles emerging as a prominent research focus. Additionally, the potential implications of nanoparticle toxicity on human circulation and the immune system may present novel avenues for future investigative pursuits.

Our research underscores the imperative of devising safer and more efficacious therapeutic strategies, while also contemplating the potential side effects these pharmaceuticals may engender. Collectively, this study provides a rigorous scientific assessment of the role of nanomedicine in HCC treatment, offering invaluable insights and direction for subsequent research endeavors and clinical applications.

Abbreviations

HCC

Hepatocellular carcinoma

NPs

Nanoparticles

EPR

Enhanced permeability and retention effect

BCLC

Barcelona Clinic Liver Cancer staging system

HBV

Hepatitis B virus

HCV

Hepatitis C virus

AFP

Alpha-fetoprotein

FDA

Food and Drug Administration

NP

Nanoparticle

RFA

Radiofrequency ablation

TCL-SPION

Thermally cross-linked superparamagnetic iron oxide nanoparticles

SCP

Single Country Publication

PEI

Polyethyleneimine

PEG

Polyethylene glycol

ASGP-R

Asialoglycoprotein receptor

GPC3

Glypican-3

GA-R

Glycyrrhetinic acid receptor

TFR

Transferrin receptor

FR

Folate receptor

NTDDS

Nanotechnology-based targeted drug delivery systems

MCA

Multiple Correspondence Analysis

WOS

Web of Science

IJN

International Journal of Nanomedicine

BM

Biomaterials

ACS

American Chemical Society

JCR

Journal Citation Reports

h-index

Hirsch index

g-index

Gini index

m-index

m-Aging index

Author contributions

LuYang designed and conducted the study, performed the primary data analysis, and drafted the initial manuscript. LeiYu made significant contributions to the interpretation of data and revision of the manuscript. Qiang Zhou, Shimin Tang, and Li Liu, provided support in data collection, literature review, and statistical analysis.Yong Li and NaLi guided the scientific direction of the research, participated in the final review of the manuscript, and are responsible for the research findings. All authors contributed to the article and approved the submitted version.

Funding

No Funding.

Data availability

All data for this study are available from Web of Science (https://www.webofscience.com).

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors have read and approved the final version of the manuscript and agree to its submission to Discover Oncology for publication.

Competing interests

The authors declare no competing interests.