Bibliometric analysis of nanomaterials in hepatocellular carcinoma treatment: research trends, knowledge structures, and emerging insights (2000–2024)

Abstract

This study analyzes the research landscape of nanomaterials in treating hepatocellular carcinoma (HCC) and examines publication trends in this field by conducting a comprehensive bibliometric analysis within the Web of Science Core Collection (WoSCC) database. Articles published from 2000 to September 16, 2024 were retrieved using a structured search formula targeting studies on nanomaterials in HCC, including nanoparticles, nanodots, nanorods, nanosheets, and nanomedicine. Only English full-text articles and reviews relevant to nanomaterial applications in HCC were considered, excluding conference abstracts and non-research items. The analysis encompasses annual publication trends, country-wise publication distribution, prominent institutions, and key journals in the field. Statistical and graphical analyses were performed using GraphPad Prism (v8.0.2) to illustrate publication trends. CiteSpace (6.2.4R) and VOSviewer (1.6.18) software were used to visualize co-citation and keyword networks, highlighting scientific knowledge structures and research hotspots. Notable advancements have emerged as a promising strategy, enabling hepatocyte-specific drug delivery to enhance therapeutic precision and minimize off-target effects. This analysis provides a comprehensive understanding of the evolution of HCC nanomaterials research, key contributing countries, major research institutions, and frequently cited keywords. The findings offer valuable insights into the field's knowledge base, emerging trends, and future directions in HCC treatment with nanomaterials.

Introduction

Nanomaterials have emerged as highly promising diagnostic and therapeutic tools in the field of hepatocellular carcinoma (HCC) research [1–3]. Due to the complexity and high fatality rate of liver cancer, developing novel methods that offer precision targeting and effective therapeutic delivery is a key imperative. Nanomaterials, characterized by their unique physicochemical properties at the nanoscale, enable targeted drug delivery, enhance imaging resolution, and provide controlled release profiles, thus overcoming the limitations of conventional HCC treatments [4–6]. Bibliometrics analysis can be applied to quantify the importance and development of nanomaterials research in HCC. It can help unravel the research trends and identify researchers and important journals that have contributed to the development of nanomaterials in the treatment of HCC. It can also shed light on global research interests and identify key aspects of nanotechnology that address HCC research needs.

Recent decades have witnessed significant growth in nanotechnology applications in HCC, with numerous studies focusing on developing nanoparticles for drug delivery and diagnostic applications. Nanomaterials such as liposomes [7–10], dendrimers [11], metal nanoparticles (e.g., gold and iron oxide) [12, 13], and polymeric nanoparticles [14, 15] have shown potential in improving the therapeutic efficacy of anti-cancer drugs. For instance, liposomes facilitate the encapsulation of hydrophobic drugs, preventing their premature degradation and reducing off-target effects [16–18]. Likewise, the photothermal properties of gold nanoparticles make them suitable for targeted cancer therapy [19–22]. These advances are reflected in an increasing number of publications in this field. Bibliometric analysis revealed an exponential increase in research over the last two decades, suggesting a strong correlation between nanotechnology applications and breakthroughs in HCC treatment. Bibliometric studies on nanomaterial applications in HCC research can analyze citation trends, publication counts, and country-specific research contributions, offering insights into the knowledge landscape of this domain. The number of research publications has risen steadily since the early 2000s, with major contributions from countries like the United States, China, and Europe, emphasizing the global interest in using nanotechnology for HCC. High-impact journals such as “Biomaterials”, “International Journal of Nanomedicine”, and “ACS Applied Materials & Interfaces” have frequently published pioneering studies, underlining the interdisciplinary collaboration between materials science, oncology, and pharmacology. Co-authorship networks reveal key researchers who have collaborated extensively, contributing to the translational impact of nanomaterial research in HCC, thus making it possible to trace significant shifts in research focus, from early-stage development to clinical application.

Furthermore, bibliometric analyses indicate a strong correlation of certain keywords such as “drug delivery,” [23, 24] “therapy,” [25–27] and “apoptosis” [28–31] with HCC research, reflecting the primary goals of enhancing drug specificity, reducing side effects, and improving patient outcomes. Keyword analysis also suggests emerging trends, such as theranostics (therapy and diagnostics) [32–36] and immunomodulation [37–40], highlighting innovative directions wherein nanomaterials facilitate not only drug delivery but also immune response modulation. The recent surge in publications on immuno-nanoparticles for HCC indicates a growing interest in combining immunotherapy with nanomaterial-based delivery systems. This approach could potentially overcome challenges related to immune evasion by HCC tumors. Given the heterogeneity of liver tumors, personalized medicine is gaining traction. Nanomaterials are poised to play a crucial role in this movement. Bibliometric analyses reveal that personalized nanomedicine research is gaining momentum, focusing on designing nanoparticles tailored to individual patient profiles. This approach is particularly valuable in HCC, given its diverse etiology and genetic landscape. Advanced bibliometric techniques, such as citation burst detection and thematic mapping, help identify emerging research fronts and influential works that shape nanomaterial applications in HCC research. These tools can highlight seminal studies or review papers that have significantly impacted subsequent research, providing a clear picture of the evolution of this field in response to clinical challenges in HCC treatment.

This study aims to investigate the integration of nanomaterials in HCC research, focusing on their impact on diagnosis, imaging, and treatment strategies. Through bibliometric analysis, the research identifies growth trends and pivotal contributions of nanomaterial applications in advancing HCC therapy. The findings highlight the significant role of nanomaterials in liver cancer research, providing a foundation to prioritize future research directions and foster sustained innovation for improved patient outcomes.

Materials and methods

Inclusion and exclusion criteria

The Web of Science Core Collection (WoSCC) database is known for its accuracy in document-type labeling, making it the optimal choice for bibliometric analysis. Accordingly, this study conducted a literature search on WoSCC, focusing on publications related to the application of nanomaterials in HCC research. The search was performed on September 16, 2024, and spanned the period from January 2000 to September 16, 2024. The search formula was constructed to ensure comprehensive coverage of relevant terms associated with both HCC and nanomaterials. The search string used was as follows:

((((((TS = ("Carcinoma, Hepatocellular")) OR TS = ("Carcinomas, Hepatocellular")) OR TS = ("Hepatocellular Carcinoma*")) OR TS = ("Carcinoma*, Liver Cell")) OR TS = ("Cell Carcinoma*, Liver")) OR TS = ("Liver Cell Carcinoma*") AND TS = (nanodot* OR nanoparticle* OR nanomaterial* OR nanotube* OR nanosheet* OR “quantum dot*” OR nanofiber* OR nanosphere* OR nanorod* OR nanowire* OR nanocrystal* OR nanocomposite* OR nanodevice* OR nanocluster* OR nanotechn* OR nanocarrier* OR nanowire* OR nanoliposome* OR nanoemulsion* OR nanocrystal* OR nanoconjugate* OR nanogels* OR nanodiamond* OR nanoporou* OR nanosilver* OR nanopore* OR nanomicell* OR nano size* OR nanomedicine* OR nanofibrou*)).

The inclusion criteria were as follows: (1) availability of full-text publications related to the application of nanomaterials in HCC; (2) article type: original research and review articles; (3) language of publication: English. The exclusion criteria were as follows: (1) publications not directly relevant to nanomaterials in HCC research; and (2) document types such as conference abstracts, news articles, and briefs, which do not provide comprehensive insights for bibliometric analysis. All selected publications were exported in plain text format to facilitate data analysis.

Research object

English literature regarding the application of nanomaterials in liver cancer treatment, published and indexed in the WoSCC database from September 16, 2000, to September 16, 2024.

Statistical analysis

To further analyze the literature and generate visual representations of scientific knowledge maps, we employed CiteSpace (v6.2.4R, 64-bit Advanced Version) and VOSviewer (v1.6.18). VOSviewer, a free software developed by Waltman et al. in 2009, is designed for analyzing large-scale bibliometric data and presenting it in the form of network maps. Built on a JAVA-based platform, VOSviewer provides a user-friendly interface for constructing bibliometric networks, such as co-authorship, citation, and co-occurrence networks. These networks are particularly effective for understanding research frontiers and influential patterns in a specific field. In this study, VOSviewer facilitated the generation of co-authorship and keyword co-occurrence maps, elucidating collaborations among researchers and highlighting frequently explored keywords at the intersection of nanomaterials and HCC.

To map co-citation networks and visualize research achievements in the field, we utilized CiteSpace (v6.2.4R), an advanced scientometric software developed by Professor Chaomei Chen. CiteSpace provides a structured framework to investigate emerging concepts and evaluate existing knowledge, offering users a comprehensive view of the knowledge domain, research frontiers, and trends. CiteSpace enables a thorough exploration of intellectual structures and thematic progressions within a research field through the construction of citation burst detection, thematic analysis, and keyword cluster mapping. This software, with its experimental framework, is especially useful for identifying research trends and predicting future directions in nanomaterial applications in HCC research.

Results

Literature selection

A total of 4392 articles were retrieved from the WoSCC database. After applying the first inclusion criterion, restricting publication years to 2000–2024, 153 articles were excluded, leaving 4239 articles. Non-research articles, including book chapters, corrections, and editorial materials, were then filtered out, removing 78 more articles and leaving 4161. The language criterion was applied next, excluding 11 non-English articles and bringing the total to 4150. Finally, duplicate entries were reviewed, but none were identified. This resulted in a final count of 4150 studies included for analysis (Fig. 1).

Fig. 1.

Schematic illustration of literature search

Annual volume of publications

The results show that the WoSCC database contains 4150 articles related to nanomaterials in HCC research, comprising 3473 research articles and 677 review papers. These publications span 93 countries and regions, 3417 institutions, and involve 16,912 authors. The number of publications has steadily increased since 2001, with annual output gradually rising over time. The publication trend can be divided into three phases. From 2001 to 2008, the field experienced slow growth, with fewer than 20 papers published annually, indicating slow development (Fig. 2). After 2009, the number of publications began to rise rapidly, with a further sharp increase after 2014, reaching its peak in 2023. This trend highlights growing research interest and accelerating progress in applying nanomaterials in HCC research over the past two decades.

Fig. 2.

The number of articles about nanomaterials in hepatocellular carcinoma across different years

Following this analysis, we examined publication trends by country over time. Research on the application of nanomaterials in HCC has expanded globally, with contributions from 99 countries and regions. Before 2006, publication volumes were similar among countries. However, after 2006, publication output increased significantly, particularly in China and the United States. This growth became more pronounced after 2011, with publication numbers surging dramatically, reaching a peak of 340 papers in 2023 (Fig. 3). These trends underscore China’s substantial and rapidly growing research capacity, reflecting its increasing prominence and strength in scientific research.

Fig. 3.

Line graph of national publications

Figure 4 presents a heatmap showing the annual publication numbers over the past decade for the top 10 countries in this field, highlighting dynamic growth in different regions. The top five countries by publication volume are China, the United States, India, Egypt, and Saudi Arabia, with China leading by a significant margin. China’s contribution is particularly noteworthy, accounting for 60.58% of all publications in this research area, far surpassing other countries. This dominant share reflects China’s prioritization of nanotechnology in biomedical research and its significant investment in HCC-related studies. The United States ranks second, followed by India, Egypt, and Saudi Arabia, each showing steady growth in research output but with a substantially smaller share than China. These trends emphasize the pivotal role China and a few other nations play in advancing nanomaterials research for HCC, fostering international progress in the field. China’s dominant presence in publication volume underscores its rapidly expanding research capacity, leadership, and commitment to pioneering innovative cancer therapies. This commitment has substantial implications for developing nanotechnology-based treatments in oncology.

Fig. 4.

Heat map of national publications

Among the top ten countries in terms of publication volume on nanomaterials research in HCC, China leads with a total citation count of 70,703, surpassing other nations (Table 1). However, China’s citation-to-publication ratio is 28.12, ranking seventh overall. This relatively low ratio suggests that while China produces a high research volume, the overall citation impact per paper is moderate, indicating a generally lower average publication quality. In contrast, the United States ranks second in both publication volume (586 papers) and total citations (27,718), with a citation-to-publication ratio of 47.30, the highest among all countries. This high ratio reflects the generally higher quality and influence of publications from the United States in this research area. China’s high publication and citation numbers are complemented by a centrality score of 0.36, underscoring its leadership role in nanomaterials research for HCC. This centrality reflects China’s substantial influence and interconnectedness within the global research landscape. China’s high publication volume, frequent citations, and key position in the collaborative network collectively position it as a leading nation in advancing this area of study. However, the citation impact per paper suggests the potential for improvement in average research quality.

Table 1.

Published literature by country

Rank	Country/region	Article counts	centrality	Percentage (%)	Citation	Citation per publication
1	China	2514	0.36	60.58	70,703	28.12
2	USA	586	0.16	14.12	27,718	47.30
3	India	313	0.2	7.54	8918	28.49
4	Egypt	259	0.07	6.24	4775	18.44
5	Saudi Arabia	177	0.17	4.27	3951	22.32
6	Iran	137	0.11	3.30	3334	24.34
7	South Korea	120	0	2.89	4516	37.63
8	Italy	96	0.12	2.31	3464	36.08
9	Germany	94	0.05	2.27	3499	37.22
10	Japan	74	0	1.78	2604	35.19

International collaboration network of different countries and institutions

The international collaboration network further illustrates differences in research partnerships (Fig. 5). The United States has strong collaborations with Western nations, including Italy, Germany, and France, indicating a well-established network. In contrast, China has closer research ties with Saudi Arabia, South Korea, and India, forming a distinct collaborative network in Asia and the Middle East. The distinct collaborative networks of China and the United States highlight different regional partnerships driving progress in the field.

Fig. 5.

Networks of country cooperation

A total of 3417 institutions have systematically published research articles on the application of nanomaterials in HCC. Among the top ten institutions ranked by publication volume, nine are based in China, while one is located in Egypt (Table 2; Fig. 6). The Chinese Academy of Sciences leads as the top institution, with 256 papers, cited 11,089 times, yielding an average citation of 43.32 per paper. The Egyptian Knowledge Bank (EKB) ranks second, also with 256 papers, accumulating 4764 citations, averaging 18.61 citations per paper. Zhejiang University ranks third, with 130 papers cited 4479 times (an average of 34.45 citations per paper), followed by Sun Yat-Sen University, with 124 papers and 3377 citations, averaging 27.23 citations per paper. This distribution underscores the prominent role of Chinese institutions in advancing nanomaterials research for HCC, reflecting China's strong commitment to exploring innovative cancer therapies through substantial research output. The significant position of the Egyptian Knowledge Bank also highlights Egypt's growing investment and impact in this field, particularly within the MENA region. Further analysis reveals a strong tendency among both domestic and international institutions to collaborate primarily with other institutions within their own country. This pattern suggests that while substantial progress has been made, the field could benefit from enhanced international collaboration, fostering more diverse perspectives and sharing of resources. Strengthening cross-border partnerships would help dismantle academic silos and accelerate advancements in nanomaterial applications for HCC. Enhanced global collaboration could foster richer innovation, unlocking the full potential for breakthroughs in cancer treatment and ultimately improving patient outcomes globally.

Table 2.

Summary of institutional published literature

Rank	Institution	Country	Number of studies	Total citations	Average citation
1	Chinese Academy of Sciences	China	256	11,089	43.32
2	Egyptian Knowledge Bank (EKB)	Egypt	256	4764	18.61
3	Zhejiang University	China	130	4479	34.45
4	Sun Yat Sen University	China	124	3377	27.23
5	Fudan University	China	97	2844	29.32
6	University of Chinese Academy of Sciences	China	83	3163	38.11
7	Huazhong University of Science & Technology	China	83	2250	27.11
8	Shanghai Jiao Tong University	China	82	2957	36.06
9	Southeast University – China	China	77	1608	20.88
10	Jilin University	China	76	3008	39.58

Fig. 6.

Networks of institutional co-operation

Publications in different journals

Table 3 and Fig. 7 present the top 10 journals with the highest publication output and citation counts in the field of nanomaterials for HCC research. Among these, the International Journal of Nanomedicine ranks as the most prolific journal, publishing 163 articles (3.93% of all publications in this area). This is followed by ACS Applied Materials & Interfaces with 81 articles (1.95%), Biomaterials with 77 articles (1.86%), and the International Journal of Pharmaceutics with 75 articles (1.81%). Biomaterials stands out with the highest impact factor (IF) of 12.8, reflecting its significant influence and reputation in the field. Notably, 90% of these leading journals are categorized in the Q1 or Q2 quartiles, highlighting the high-quality venues where much of the research on nanomaterials in HCC is published. The data reveal a concentration of HCC-related nanomaterials research in a select group of high-impact journals, with the International Journal of Nanomedicine standing out due to its high publication volume. The prevalence of Q1/Q2 quartile journals further underscores the high quality and relevance of research in this field, highlighting the priority accorded to nanomaterials for HCC therapy by high-tier publications in nanotechnology and biomedical sciences. This concentration of high-impact journals reflects the growing recognition and scientific interest in leveraging nanomaterials for cancer treatment.

Table 3.

Summary of journal publications

Rank	Journal	Article counts	Percentage (4150)	IF	Quartile in category
1	International Journal of Nanomedicine	163	3.93	6.6	Q1
2	ACS Applied Materials & Interfaces	81	1.95	8.3	Q1
3	Biomaterials	77	1.86	12.8	Q1
4	International Journal of Pharmaceutics	75	1.81	5.3	Q1
5	Journal of Nanobiotechnology	62	1.49	10.6	Q1
6	RSC Advances	62	1.49	3.9	Q2
7	Journal of Controlled Release	61	1.47	10.5	Q1
8	Journal of Biomedical Nanotechnology	60	1.45	2.9	Q4
9	Journal of Materials Chemistry B	55	1.33	6.1	Q1
10	Journal of Drug Delivery Science and Technology	53	1.28	4.5	Q1

Fig. 7.

Density map of journal publications

Journal impact is often assessed by co-citation frequency, which indicates a journal's influence within the scientific community. Figure 8 and Table 4 show that Biomaterials is the most co-cited journal in the field of nanomaterials for HCC research, with 2261 co-citations. Journal of Controlled Release and ACS Nano follow, with 1978 and 1678 co-citations, respectively. Among the top 10 most co-cited journals, Advanced Drug Delivery Reviews is notable, with 1407 co-citations and the highest IF among the top 10, at 15.2. All of these highly co-cited journals fall within the Q1 quartile, underscoring their prominence and credibility in the field. The dominance of Q1 journals among the most co-cited sources underscores their substantial influence in shaping advancements in HCC nanomaterial applications. This high co-citation frequency reflects the recognition and authority these journals hold in disseminating impactful findings within this research area.

Fig. 8.

Co-citation network map of journals

Table 4.

Co-citation table of journals

Rank	Cited Journal	Co-citation	IF (2023)	Quartile in category
1	Biomaterials	2261	12.8	Q1
2	J Control Release	1978	10.5	Q1
3	Acs Nano	1678	15.8	Q1
4	Int J Nanomed	1669	6.6	Q1
5	Cancer Res	1456	12.5	Q1
6	Adv Drug Deliver Rev	1407	15.2	Q1
7	Acs Appl Mater Int	1383	8.3	Q1
8	Int J Pharm	1352	5.3	Q1
9	Hepatology	1248	12.9	Q1
10	Proc Natl Acad Sci USA	1246	9.4	Q1

Figure 9 illustrates the thematic distribution of academic publications through dual-map overlay (Fig. 9), where color-coded paths represent citation relationships. Citing journals are on the left, and cited journals on the right. Our analysis reveals two primary citation paths. The first major path shows that research published in journals within the Molecular/Biology/Genetics domain is predominantly cited by journals in the Molecular/Biology/Immunology field. The second path indicates that Chemistry/Materials/Physics journals are frequently referenced by journals in the Physics/Materials/Chemistry category. These citation patterns highlight strong interdisciplinary connections, where foundational research in molecular biology and genetics informs advancements in immunology, while chemistry and materials science studies drive further research in physics and chemistry-focused materials sciences. This thematic crossover underscores the interrelated nature of these disciplines in advancing nanomaterial applications for HCC research.

Fig. 9.

Dual map of journals

Famous authors in the fields of nanomaterials research in HCC

Table 5 lists the top 10 most prolific authors in nanomaterials research for HCC, who collectively have published 230 articles (5.54% of all papers in this area). Liu Xiaolong leads with 29 publications, followed by Li Jing (26 articles), Li Guiyin (24 articles), and Tian Jie (24 articles). These leading authors have significantly contributed to the field, reflecting their expertise and sustained research focus on HCC-related nanomaterials. Figure 10 visualizes the collaborative network among these authors using CiteSpace, highlighting strong research connections and collaborations within a cohesive and interactive scholarly community. This high level of collaboration strengthens the field, facilitates the exchange of innovative ideas, and accelerates the development of nanotechnology-based cancer treatments.

Table 5.

Author's publications and co-citation table

Rank	Author	Count	Rank	Co-cited author	Citation
1	Liu, Xiaolong	29	1	Llovet JM	593
2	Li, Jing	26	2	Zhang Y	419
3	Li, Guiyin	24	3	Liu Y	368
4	Tian, Jie	24	4	Wang Y	368
5	Liu, Yang	22	5	Jemal A	364
6	Wang, Yan	22	6	Li Y	335
7	Liang, Jintao	21	7	Wang J	306
8	Yang, Xiangliang	21	8	Bruix J	305
9	Zhang, Yu	21	9	Zhang L	301
10	Li, Yan	20	10	Li J	290

Fig. 10.

Cooperation network of authors

Figure 11 and Table 5 identify the top 10 most frequently co-cited and cited authors in nanomaterials research for HCC. Among 116 authors with over 50 citations, their work demonstrates high recognition and influence in this research area. The largest nodes in the co-citation network correspond to the most frequently cited authors, including Llovet JM with 593 citations, Zhang Y with 419 citations, and Liu Y with 368 citations. Their significant citation counts underscore their foundational contributions and the lasting impact of their research on the development of nanomaterials for HCC. This co-citation network reflects the authors’ central roles in shaping the field and the reliance of subsequent studies on their findings. The prominence of these researchers suggests their work has provided essential insights and methodologies that continue to influence advancements in nanotechnology for HCC treatment.

Fig. 11.

Co-citation network of authors

Co-cited literature in the fields

The co-citation network of references in the field of nanomaterials for HCC research, covering the period from 2000 to 2024, consists of 1528 nodes and 5985 links (Fig. 12). Table 6 lists the top 10 most co-cited articles, with the most co-cited article being a publication from Nature Reviews Gastroenterology & Hepatology titled "A Global View of Hepatocellular Carcinoma: Trends, Risk, Prevention and Management" by Yang Ju Dong et al. This highly cited paper identifies HCC as the fourth most common cause of cancer-related deaths globally, highlighting major risk factors such as chronic hepatitis B and C infections, alcohol abuse, metabolic liver disease (especially non-alcoholic fatty liver disease), and dietary toxins like aflatoxin and aristolochic acid. Importantly, these are preventable risk factors, underscoring the potential of risk prevention strategies to reduce the global HCC burden. The article emphasizes that regular HCC surveillance and early detection could enhance treatment opportunities. Despite this, surveillance remains underutilized, even in countries with ample healthcare resources. Early-stage HCC can be treated with curative intent using local ablation, surgical resection, or liver transplantation, with treatment decisions dependent on tumor characteristics, the degree of liver function impairment, patient age, comorbidities, available healthcare resources, and local expertise. Transarterial therapies are suited for intermediate-stage HCC, while kinase and immune checkpoint inhibitors have shown efficacy in advanced cases. The article suggests that prevention strategies, global goals for viral hepatitis eradication, and improved HCC surveillance and treatment could collectively reduce the global HCC burden over the coming decades.

Fig. 12.

Co-cited network of literature

Table 6.

Co-citation table of literature

Rank	Title	Journal	Author(s)	Total citations
1	A global view of hepatocellular carcinoma: trends, risk, prevention and management	Nature Reviews Gastroenterology & Hepatology	Yang JD	98
2	Cancer nanomedicine: progress, challenges and opportunities	Nature Reviews Cancer	Shi JJ	65
3	Challenges in liver cancer and possible treatment approaches	Biochimica et Biophysica Acta-Reviews on Cancer	Anwanwan D	59
4	Simultaneous inhibition of growth and metastasis of hepatocellular carcinoma by co-delivery of ursolic acid and sorafenib using lactobionic acid modified and pH-sensitive chitosan-conjugated mesoporous silica nanocomplex	Biomaterials	Zhao RR	58
5	Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial	Lancet	Kudo M	55
6	Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma	New England Journal of Medicine	Finn RS	51
7	Asialoglycoprotein receptor mediated hepatocyte targeting—strategies and applications	Journal of Controlled Release	DSouza AA	49
8	The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects	Signal Transduction and Targeted Therapy	Tang WW	46
9	Molecular therapies and precision medicine for hepatocellular carcinoma	Nature Reviews Clinical Oncology	Llovet JM	43
10	Engineering precision nanoparticles for drug delivery	Nature Reviews Drug Discovery	Mitchell MJ	43

The second most co-cited article, "Cancer Nanomedicine: Progress, Challenges, and Opportunities" by Shi Jinjun, published in Movement Disorders, addresses the limitations of conventional cancer therapies and the role of nanotechnology in enhancing cancer treatment safety and efficacy. Despite substantial technological advances, cancer nanomedicine faces major challenges due to the complexity and heterogeneity of tumor biology, limited understanding of nano-bio interactions, and challenges in chemistry, manufacturing, and controls for clinical translation and commercialization. This review discusses key advancements, challenges, and opportunities in cancer nanomedicine, focusing on innovative engineering approaches that leverage growing insights into tumor biology and nano-bio interactions to develop more effective cancer nanotherapies. These two foundational papers underscore the pressing need for preventive and advanced treatment strategies in HCC and the potential of nanotechnology to address key limitations in conventional cancer therapy.

Our co-citation reference clustering and temporal clustering analysis, shown in Fig. 13, revealed distinct phases in research focus within the field of nanomaterials for HCC. Early research hotspots included superparamagnetism (cluster 7), carbon nanotubes (cluster 8), targeting metabolic reprogramming (cluster 9), and SIRT7 inhibitors (cluster 10). These foundation topics paved the way for understanding how nanomaterials interact with cellular processes and metabolic pathways in HCC.

Fig. 13.

Clustering and peak map of co-cited literature

As the field progressed, research focus expanded to new applications and techniques. Middle-phase research hotspots include magnetofection (cluster 4), surface immobilization (cluster 5), quantum dots (cluster 6), ultrasmall superparamagnetic iron oxide (USPIO) (cluster 12), biotechnology (cluster 13), and apolipoprotein A-I (cluster 15). These areas highlight advancements in nanoparticle delivery systems, imaging techniques, and bioengineering methods aimed at enhancing HCC therapy efficacy and precision. Current trends and hotspots in HCC-related nanomaterials focus on topics with strong therapeutic and genetic implications driving continued innovation in this field. Key areas include hepatocellular carcinoma itself (cluster 0), arsenic trioxide (cluster 1), siRNA (cluster 2), sorafenib (cluster 3), exosomes (cluster 11), and CRISPR/Cas9 (cluster 14). These topics reflect a growing interest in targeted molecular and genetic therapies, leveraging nanomaterials for precision oncology. The focus on CRISPR/Cas9 and siRNA, in particular, highlights a trend toward gene-editing techniques and RNA interference, offering innovative therapeutic approaches to combat HCC. This clustering analysis provides a clear timeline of evolving research priorities, underscoring both foundational studies and emerging trends shaping the future of nanomaterial applications in HCC treatment.

High-frequency keywords in the publications

Analyzing keywords provides an overview of a research field’s current state and future directions. Our examination of keyword co-occurrence in VOSviewer revealed key trends and focal points in nanomaterials research for HCC. The most frequently occurring keywords were drug delivery (587 occurrences), therapy (453), apoptosis (450), doxorubicin (369), and sorafenib (286) (Table 7; Fig. 14). After filtering irrelevant keywords, we constructed a network in VOSviewer with 172 keywords that appeared at least 37 times, resulting in five distinct clusters. These clusters highlight the primary thematic areas within the field, showcasing research topics and emerging directions.

Table 7.

High-frequency keyword table

Rank	Keyword	Counts	Rank	Keyword	Counts
1	Drug-delivery	587	10	Oxidative stress	176
2	Therapy	453	11	Nanomedicine	173
3	Apoptosis	450	12	Release	156
4	Doxorubicin	369	13	Photothermal therapy	149
5	Sorafenib	286	14	Iron-oxide nanoparticles	142
6	Chemotherapy	264	15	Toxicity	137
7	Gold nanoparticles	231	16	Diagnosis	136
8	Cytotoxicity	222	17	Metastasis	136
9	Co-delivery	195	18	Targeted delivery	135

Fig. 14.

Network and density map of high-frequency keywords

Cluster 1 (red)—mechanisms and pathways

This cluster comprises 52 keywords, including apoptosis, metastasis, activation, inhibition, sorafenib, angiogenesis, cell death, autophagy, extracellular vesicles, ferroptosis, gene therapy, hepatic stellate cell, inflammation, mechanism, nanomedicine, metabolism, progression, resistance, ROS, and targeted therapy. This group focuses on molecular mechanisms and pathways related to HCC progression and treatment. Key concepts such as apoptosis, cell death, and autophagy highlight the cellular processes involved in cancer response to therapies. Notably, keywords like sorafenib, a widely used targeted drug for HCC, indicate significant research interest in drug resistance and mechanisms of action. Terms like inflammation and hepatic stellate cell underscore the role of liver-specific cells and immune processes in HCC. This cluster also emphasizes targeted therapies, with efforts to design nanomedicines that interact precisely with cancer cells, potentially overcoming resistance mechanisms and achieving better treatment outcomes.

Cluster 2 (green)—drug delivery systems

The second cluster comprises 49 keywords, primarily focusing on drug delivery systems, such as drug delivery, targeted delivery, co-delivery, nanocarriers, antitumor, biodistribution, cisplatin, design, chemotherapy, formulation, micelles, peptide, multidrug resistance, stability, liposome, and efficacy. This group reflects extensive research on developing and optimizing nanocarriers for delivering therapeutic agents in HCC. Researchers are exploring various formulations, including micelles, liposomes, and peptides, to enhance the stability and bioavailability of cancer drugs. The prominence of cisplatin and other chemotherapy agents indicates interest in combining traditional chemotherapy with nanotechnology for targeted delivery. The use of co-delivery systems and approaches to overcome multidrug resistance demonstrates efforts to maximize treatment efficacy while minimizing side effects.

Cluster 3 (blue)—diagnostic and biomarker development

This cluster, consisting of 30 keywords, focuses on diagnostic tools and biomarker identification, including terms like biomarker, protein, gold nanoparticle, DNA, antibody, surface, diagnosis, assay, immunoassay, biosensor, nanocomposite, aptamer, carbon nanotubes, fluorescence, graphene, identification, nanocrystals, and strategy. Diagnostic approaches are crucial for early detection and monitoring of HCC progression. The inclusion of gold nanoparticles, carbon nanotubes, and graphene shows the application of various nanomaterials in biosensor development, allowing for sensitive and specific detection of HCC-related biomarkers. Advances in immunoassays and aptamers further underscore the push towards precision diagnostics, while fluorescence-based methods continue to provide valuable insights into cellular interactions.

Cluster 4 (yellow)—imaging and theranostics

This cluster includes 26 keywords related to imaging and theranostic applications, including therapy, iron oxide nanoparticle, contrast agent, magnetic resonance imaging, microphase, dendritic cell, embolization, immunotherapy, model, survival, photothermal therapy, theranostic, and biomedical application. The use of iron oxide nanoparticles as magnetic resonance imaging (MRI) contrast agents highlights the role of nanomaterials in non-invasive imaging techniques, crucial for accurate diagnosis and monitoring. Theranostics, which combines therapy and diagnostics, is also a key focus. Keywords like photothermal therapy suggest innovative strategies for targeted cancer cell destruction. This cluster reflects the dual-purpose role of nanomaterials, serving as both therapeutic agents and imaging tools to guide and monitor treatment responses.

Cluster 5 (purple)—toxicity and cellular uptake

The fifth cluster comprises 15 keywords, including cytotoxicity, HepG2, mechanism, anticancer, cellular uptake, complex, green synthesis, silica nanoparticles, and size. This group addresses concerns related to nanomaterial safety and effectiveness, particularly in the context of HCC research. The frequent appearance of HepG2 cell line reflects its importance in assessing nanoparticle biocompatibility and anticancer potential. The terms green synthesis and silica nanoparticles highlight environmentally friendly production methods and alternative materials for reducing toxicity while maintaining effectiveness.

Finally, using CiteSpace, we visualized the temporal evolution of research hotspots through a burst analysis (Fig. 15). The resulting volcano plot shows emerging topics such as doxorubicin, magnetic resonance imaging, gene therapy, alpha therapy, silver nanoparticles, liver fibrosis, and cancer therapy. These trends underscore the growing interest in advanced therapeutic approaches and precision diagnostic tools in HCC treatment. The emphasis on doxorubicin and gene therapy indicates ongoing efforts to refine targeted and gene-based treatments. Research on liver fibrosis highlights the need to address HCC's complex pathology. Overall, this analysis reveals a rapidly evolving field with a broadening scope, aiming to improve the treatment and diagnosis of HCC.

Fig. 15.

Peak map and clustering of keyword

Using CiteSpace, we identified the top 50 most reliable citation bursts in the field of nanomaterials research for HCC. The most highly cited reference is an article by Peer D et al., published in Nature Nanotechnology, titled “Nanocarriers as an emerging platform for cancer therapy.” This review highlighted innovative strategies in cancer treatment using targeted nanocarriers for drug delivery. Traditional drug delivery methods rely on the diffusion of drugs into cells, but the study suggests that nanocarriers, particularly those designed to be internalized by cancer cells, offer a more effective alternative. This approach leverages the overexpression of certain receptors on cancer cells, which are essential for their rapid metabolism. By targeting these receptors with specific growth factors or vitamins, the drugs are directed precisely to cancerous tissues. The paper also discusses the challenges of treating circulating cancer cells, such as those found in leukemia and lymphoma. For these cells, therapies that target surface antigens with high affinity, paired with carriers that have a long circulating half-life, have been suggested to be the most promising. The authors point to successful examples such as Abraxane, an albumin-bound paclitaxel nanoparticle approved for metastatic breast cancer treatment, and Bevacizumab, an anti-VEGF monoclonal antibody that inhibits angiogenesis in colorectal cancer. Despite these advances, the paper emphasizes the ongoing issue of drug resistance, as cancer cells can expel therapeutic agents, diminishing their efficacy over time. The study underscores the importance of continued innovation in overcoming these challenges to improve the success rate of cancer therapies. A citation analysis of the 50 most cited references, spanning from 2000 to 2024, reveals a consistent and enduring interest in HCC nanomedicine research over the past two decades. Notably, 19 of these references are currently experiencing citation peaks (Fig. 16), indicating sustained and possibly increasing interest in this research area. This trend suggests that nanomaterials for liver cancer remain a highly relevant topic, likely to continue shaping future studies in the field.

Fig. 16.

Burst map of cited literature

Additionally, CiteSpace analysis identified 546 burst keywords, representing research topics that gained substantial attention over a short period. Focusing on the top 50 strongest burst keywords (Fig. 17) revealed current research hotspots and potential future directions in applying nanomaterials for HCC. These keywords encompass liver-specific targeting mechanisms, nanocarrier types, therapeutic strategies, and biomolecular interactions crucial for enhancing the efficacy and specificity of liver-targeted therapies. The prominence of terms such as ASGPR, hepatocyte targeting, and galactose-modified nanocarriers points to a strong interest in receptor-mediated approaches. These approaches leverage the hepatocyte-specific characteristics to improve therapeutic precision. Furthermore, emerging keywords reflect an ongoing exploration of advanced materials, such as biodegradable nanoparticles, lipid-based carriers, and polymeric micelles. Researchers are investigating these materials for their potential in drug delivery systems tailored to the liver’s microenvironment. Concepts like drug release kinetics, cellular internalization, and immunomodulation underscore efforts to optimize nanoparticle behavior in vivo. This optimization aims to ensure sustained drug release, enhanced uptake by target cells and minimized immune responses that could compromise therapeutic effectiveness. Keywords related to preclinical and clinical evaluations, such as toxicity assessment, pharmacokinetics, and therapeutic efficacy, indicate the field’s translational focus. Researchers are increasingly concentrating on transitioning ASGPR-targeted therapies from laboratory settings to clinical applications. The emphasis on these aspects demonstrates an understanding of the complex requirements for effective HCC treatments and a commitment to developing nanomaterials that can safely navigate the human body’s complexities. Clinical implications and potential applications beyond drug delivery are also highlighted, as demonstrated by keywords like diagnostic imaging and biomarker identification. These topics illustrate that ASGPR-targeted nanomaterials hold promise not only as therapeutic agents but also as tools for early diagnosis and monitoring of liver disease progression. The emphasis on diagnostic applications highlights a broader trend toward integrating nanotechnology into various aspects of personalized medicine for HCC. The citation burst references and keywords collectively highlight the field's dynamic nature and the central role of ASGPR-mediated hepatocyte targeting in HCC research. As new nanomaterials and a more nuanced understanding of receptor-ligand interactions emerge, the significance of this strategy is expected to grow. The field’s trajectory suggests a promising future for nanomedicine in HCC, with ASGPR-targeted approaches leading the way toward more effective and patient-specific treatments.

Fig. 17.

Burst map of keywords

Discussion

Hepatocellular carcinoma research leveraging nanomaterials is rapidly advancing, driven by significant contributions from China and the US. The field has transitioned from fundamental studies on apoptosis and autophagy to cutting-edge therapies like gene editing (CRISPR/Cas9) and siRNA-based treatments. ASGPR-targeted nanocarriers have emerged as a key innovation, offering precise drug delivery with reduced side effects. Advances in diagnostics, including imaging and biomarkers, have also improved early detection and disease monitoring. The growth of this field, fueled by global collaborations, highlights the transformative potential of nanotechnology in personalized, targeted HCC treatment, paving the way for more effective and innovative cancer therapies.

A comprehensive analysis of publication trends offers a global perspective on nanomaterials research for HCC, revealing a geographically diverse landscape with contributions from 99 countries [32–36]. China has emerged as a dominant force, accounting for over 60% of all publications. This reflects the country’s prioritization of nanotechnology in biomedical research. China’s robust collaboration network within Asia and the Middle East further strengthens its regional influence. The United States ranks second in publication volume and boasts a higher citation-to-publication ratio, indicating stronger collaborations with Western nations, forming distinct research hubs that drive field advancements. This geographical distribution highlights China’s substantial investment in the field, underscoring its commitment to developing cancer therapies with potential global impact. While China leads in publication volume, the United States’ higher citation impact suggests that American research may yield more highly recognized findings, reflecting different priorities and methodologies that characterize each country’s scientific approach.

An analysis of leading institutions reaffirms China’s dominant position in HCC-related nanomaterials research. Nine of the top ten institutions are located in China [27, 41–48], with the Chinese Academy of Sciences ranking highest in terms of publication volume and citation impact. Other prominent Chinese institutions, such as Zhejiang University and Sun Yat-Sen University, also feature among the top institutions. Egypt’s inclusion among the top institutions highlights its growing role in Middle Eastern and North African research contributions. However, despite substantial publication output, international collaborations remain limited, with most institutions preferring domestic partnerships. Strengthening cross-border collaborations could enrich the field by integrating diverse perspectives and resources, facilitating faster innovation in nanomaterials applications for HCC. This collaborative potential represents an untapped opportunity to expand the field’s impact on a global scale.

An analysis of key journals and co-citation networks reveals that research on HCC-related nanomaterials is concentrated in high-impact journals, such as *Biomaterials* and the *International Journal of Nanomedicine*. This concentration reflects the increasing scientific and clinical relevance of this field. The prominence of these high-tier publications emphasizes the importance of nanotechnology in biomedical applications. Notably, these journals’ Q1 and Q2 rankings attest to the high quality of research being published. Furthermore, the high co-citation rates among these journals reinforce their influence in advancing HCC nanomaterials research.

A thematic review of key research topics identifies five primary clusters: molecular mechanisms and pathways, drug delivery systems, diagnostic and biomarker development, imaging and theranostics, and toxicity and cellular uptake. Research focused on molecular mechanisms in HCC emphasizes cellular pathways like apoptosis and autophagy, highlighting the potential of nanomaterials to precisely target cancer cells, improving treatment efficacy. Drug delivery systems remain a major focus, as nanomaterials like micelles, liposomes, and peptides are being optimized for stability and bioavailability [49, 50]. Efforts to address challenges in multidrug resistance through co-delivery systems indicate ongoing efforts to maximize therapeutic effects while minimizing side effects. Diagnostic and imaging techniques, including the use of biosensors and iron oxide nanoparticles for MRI, reflect a strong interest in precision medicine, enabling non-invasive monitoring of disease progression. The diverse research clusters illustrate the versatility of nanomaterials in addressing various aspects of HCC management, from diagnosis to treatment.

Temporal clustering analyses reveal evolving research phases, with earlier studies focusing on carbon nanotubes and magnetic nanoparticles, and recent studies exploring genetic therapies, such as CRISPR/Cas9, siRNA, and targeted molecular drugs like sorafenib. The use of gene-editing techniques and RNA interference reflects a paradigm shift towards molecular-level interventions targeting HCC’s genetic underpinnings. This novel approach offers personalized treatment pathways, aligning with the principles of precision oncology. By tailoring treatments to individual tumor characteristics, researchers aim to overcome the limitations of conventional one-size-fits-all therapies, ultimately enhancing treatment efficacy and patient outcomes. Finally, burst analysis reveals emerging trends poised to shape future research in HCC nanomaterials. Doxorubicin, gene therapy, and liver fibrosis are identified as key areas of interest, underscoring the importance of combining traditional therapies with novel techniques. Research on liver fibrosis highlights the complex pathology of HCC and the need to address underlying conditions that exacerbate disease progression. The clinical applications of these findings hold promise for enhancing HCC treatment, potentially leading to more effective interventions with fewer side effects.

Moreover, the field’s focus on overcoming challenges such as multidrug resistance through novel drug delivery systems and co-delivery approaches has direct implications for clinical practice. By optimizing nanocarriers like micelles, liposomes, and peptides for stability and bioavailability, researchers aim to enhance the efficacy of existing chemotherapies and reduce side effects, potentially offering more effective and less toxic treatments for HCC patients.

Furthermore, ongoing research into gene therapies and molecular-level interventions is paving the way for precision oncology. This shift towards personalized treatment strategies, tailored to the genetic characteristics of individual tumors, aligns with current clinical trends prioritizing individualized care for better therapeutic outcomes. As global collaborations continue to strengthen, the integration of diverse research perspectives promises to accelerate the clinical translation of these innovative nanomaterials. This, in turn, will bring more effective and less invasive treatments for HCC within reach.

Conclusion

The analysis of publications on nanomaterials for HCC reveals a dynamic and rapidly evolving field characterized by an increasing global research output, especially prominent in China and the United States. China's substantial volume of research reflects its leadership and commitment to advancing nanotechnology in HCC. While China’s citation impact per paper is moderate, its significant contributions to the field are undeniable. Research trends indicate a transition from foundational studies on mechanisms, such as apoptosis and autophagy, to innovative therapeutic approaches, including gene therapy, CRISPR/Cas9, and siRNA-based treatments. The development of advanced drug delivery systems, particularly ASGPR-targeted nanocarriers for hepatocyte-specific therapy, holds promise for improving therapeutic precision. These nanocarriers enhance drug uptake by target cells while minimizing off-target effects. Diagnostic advancements in imaging and biomarker detection underscore nanotechnology’s potential in early detection and monitoring of HCC progression. Collaborative networks further emphasize the importance of international partnerships to foster diverse perspectives and innovation. Overall, nanomaterials research for HCC shows strong potential for transforming cancer therapy, promising more effective, targeted, and personalized approaches to address the complex pathology of liver cancer. The rapid development of this field has driven innovations in treatment methods and therapeutic systems, providing significant guidance for clinical liver cancer treatment.

Author contributions

X.H. conceived the idea and wrote the original draft. X.J. searched the literature and analyzed the data. W.Z. and J.L. helped analyze the data and provided valuable advice. X.H. and X.J. co-wrote the manuscript. All the authors read and approved the final manuscript.

Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Declarations

Competing interests

The authors confirm that there is no Competing interests.