Mapping evolution and trends of cell membrane-coated nanoparticles: A bibliometric analysis and scoping review

2.1 Data source and retrieval strategies

The publications from January 2011 to December 2023 were retrieved from the Web of Science Core Collection (WoSCC) database. The research employed was as follows: TI = (“cell membrane coated” OR “membrane-coated” OR “cell membrane*” OR “membrane camouflage*”) AND TI = (“nanoparticle” OR “nanomaterial” OR “nanomedicine” OR “nano*”). Articles and reviews specifically focused on the field of CMNPs were included. We excluded meeting abstracts, corrections, proceedings papers, editorial materials, book chapters, and retracted publications. The publication language was restricted to English. This refined approach resulted in 780 publications being selected for detailed analysis (Figure 1).

Figure 1

Flow chart of literature search and screening.

2.2 Data extraction and analysis

Two independent researchers extracted the publications from the WoSCC database in “Plain Text” format, including “Full Records and References.” The bibliometric analysis of the included studies was performed using CiteSpace 6.2.R3 Advanced, VOSviewer 1.6.19, and the R Package bibliometrix 4.1.2. Each of these three tools provides unique functionalities and insights into various aspects of the data [22,23].

CiteSpace 6.2.R3 Advanced [24] was utilized to perform collaboration network analysis (countries, institutions, and authors), co-citation analysis (authors and references), dual-map of journals, and citation burst detection for keywords. This tool allows us to gain insights into the intellectual structure of the field, identify pivotal papers, and track the evolution of research themes over time. The parameters of CiteSpace were set as follows: time span (from January 2011 to December 2023), time slice (1 year per slice), links (strength: cosine; scope: within slices), selection criteria (g-index, k = 2), and pruning (Pruning Sliced Networks and Minimum Spanning Tree).

VOSviewer (version 1.6.19) [25] was employed to create a co-occurrence map of institutions using the LinLog/modularity method, which allows us to generate visual representations of influential institutions in the field.

The R Package Bibliometrix (version 4.1.2) [26] was used to visualize countries’ collaboration world map, countries’ production over time, affiliations’ production over time, and the three-field plot. By employing Bibliometrix, we can conduct statistical tests and create interactive visualizations.

2.3 Chart interpretation

3.1 Global trend in publication outputs and citations

Among the 780 publications, there were 635 (81.41%) articles and 145 (18.59%) reviews. According to the “WOS Citation Report,” the cumulative number of citations for these documents is 15,292, with an average of 37.434 citations per article and an H-index of 98, showing a steady upward trend in annual citations. Figure 2a illustrates the statistics of annual publications, showing a consistent increase in the number of papers published each year. By fitting the data, a statistically significant relationship between the year and the number of publications and citations is observed (Figure 2b). The fitted curves predict approximately 350 publications in 2024, with a citation frequency of around 14,280. The trend suggests that the literature and citations on CMNPs will continue to increase over the next decade.

Figure 2

The number of annual publications (a) and the sum of annual citations (b) in studies of CMNPs from 2011 to 2023.

3.2 Timeline of CMCP

Through a comprehensive literature analysis, we organized a timeline diagram depicting the development of various cell membranes (Figure 3). The timeline begins in 2011 with the publication of the first article on erythrocyte membrane-encapsulated nanoparticles in Proceedings of the National Academy of Sciences of the United States of America [10]. In 2014, Zhang et al. further expanded the field by proposing cancer CMNPs for cancer therapy [27]. In 2015, bacterial CMNPs [28] and platelet membrane-encapsulated nanoparticles [29] were proposed. In 2016, new preparation methods for leukocyte membranes [30] and stem cell membranes [31] were proposed, adding to the repertoire of CMNP techniques. Zhang et al. continued their pioneering work in 2017 by proposing hybrid CMNPs [32], which combine membranes from different cell types to leverage multiple functionalities. The field saw further innovation in 2019 with the development of nanoparticle preparation methods based on exosome membrane encapsulation [33]. Two years later, Zhang et al. proposed a preparation method utilizing mitochondrial membranes, which opened new avenues for targeting cellular energy processes [34]. Most recently, Liu et al. published a groundbreaking preparation of plasma membrane-encapsulated nanoparticles in Advanced Materials, further advancing the field of CMNPs [35].

Figure 3

The timeline of CMNP research.

3.3 Authoritative country/region analysis

A total of 32 countries contributed to the publication of CMNP research. The top ten countries, based on the number of publications, are shown in Figure 4a. China leads with the highest number of publications (n = 590), citations (n = 242.16), open-access papers (n = 246), and H‐index (n = 81). Analyzing the publication trends over time, China and the United States exhibit a more pronounced increase in articles than other countries (Figure 4b). In terms of the multiple country publication (MCP) ratios, which represent the proportion of collaborative publications between multiple countries to the total publications from that country, Finland (85.7%), Australia (83.3%), and Saudi Arabia (75%) are notable. Although China has the highest number of MCPs (n = 86), its MCP ratio is relatively low due to the high overall number of publications (n = 564) (Table 1). The countries’ collaboration world map highlights that China has the highest level of collaboration with the United States (n = 58), followed by collaborations between China and Singapore (n = 13) (Figure 4c). This extensive international collaboration underscores the global interest and cooperative efforts in advancing CMNP research.

Figure 4

Analysis of countries/regions engaged in CMNP research. (a) Top ten countries/regions with the largest number of publications; (b) top ten countries/regions with the largest number of publications over time; and (c) countries’ collaboration world map.

3.4 Authoritative institution analysis

The publications included in this study were contributed by 729 institutions. The top ten institutions regarding the amounts of publications are illustrated in Figure 5a. Notably, eight out of these ten leading institutions in terms of publications are based in China, while the remaining two are from the United States. The top three institutions are University of California System (n = 73, 9.3%), University of California San Diego (n = 70, 8.9%), and Chinese Academy of Sciences (n = 68, 8.7%). When examining the publication trends over time, the University of California System and the University of California San Diego exhibit a more significant growth rate compared to the other institutions (Figure 5b). This indicates a robust and increasing contribution from these institutions to the field of CMNP research. Collaboration between institutions appears to be more extensive than between countries, as shown in Figure 5c. The Chinese Academy of Sciences, in particular, maintains close collaboration with numerous Chinese universities and research centers, as well as with institutions in the United Kingdom, the United States, and other countries and regions.

Figure 5

Analysis of institutions engaged in CMNP research. (a) Top ten institutions with the largest number of publications; (b) top ten institutions with the largest number of publications over time; and (c) institutions’ collaboration network.

3.5 Authoritative author analysis

The 780 included studies were authored by 3,640 researchers. The top three most productive authors are Liangfang Zhang (n = 70), Ronnie H Fang (n = 55), and Weiwei Gao (n = 50) (Table 2). As depicted in the author’s co-occurrence network map (Figure 6a), Liangfang Zhang demonstrates the most significant collaborative interactions with other authors, having a centrality score of 0.04. This centrality indicates his pivotal role in the research network surrounding CMNPs. Figure 6b illustrates the authors’ co-citation network map, highlighting the top three influential authors in the CMNP research area: Prof. Ronnie H Fang from the United States, Prof. Che-Ming J Hu from Taiwan, China, and Prof. Lang Rao from China. To provide a comprehensive understanding of the relationships among authors, their respective countries, and key research themes, a three-field plot is presented in Figure 6c. The visualization reveals that leading experts in CMNP research predominantly come from China and the United States, emphasizing the significant contributions from these countries to the field.

Figure 6

Analysis of authors engaged in CMNP research. (a) Author’s co-occurrence network; (b) authors’ co-citation network; and (c) the three-field plot; middle field: country; left field: authors; and right field: keywords.

3.6 Journal analysis

The 780 papers included in this study were published across 185 journals. Information regarding the top ten academic journals in this field is summarized in Table 3. The journal ACS Nano, with an impact factor of 15.8 in 2023, published the greatest number of papers (n = 34), followed by ACS Applied Materials Interfaces (32 publications, IF = 8.3), and Advanced Functional Materials (31 publications, IF = 18.5). Among the top ten journals, night was classified within the Q1 division of the Journal Citation Reports (JCR), and seven of these journals had an impact factor exceeding 10. The dual-map overlay of journals in Figure 7 illustrates the topic distribution and citation relationships among journals. There are two different citation paths. Two pink citation paths indicate that research published in molecular/biology/genetics journals is frequently cited by research in physics/materials/chemistry journals. This suggests an interdisciplinary impact where biological research findings influence materials science and chemistry studies. The yellow citation path indicates that research in molecular/biology/genetics journals is frequently cited by research in molecular/biology/immunology journals, highlighting the intrinsic connections between biological and biomedical sciences.

Figure 7

The dual-map overlay of journals in the field of CMNP research.

3.7 Reference analysis

Timeline analysis of reference co-citations provides insight into the evolution of research priorities, as well as identifies the most essential core papers (Table S1). The clustering is relatively concentrated (Q = 0.6519, S = 0.8822). According to the categorization analysis of clusters, the main subjects of references include synovial macrophage (#0), neuronal cellular nanosponge (#4), erythrocyte membrane-camouflaged polymeric nanoparticle (#9), and leucocyte membrane-coated Janus microcapsule (#13). In addition, references focus on the treatment of colorectal cancer (#2) and pulmonary inflammation (#5). Furthermore, the recent occurrence of clusters, such as #0 synovial macrophage (2018), #3 tumor cell (2018), and #4 neuronal cellular nanosponge (2019), suggests that these are emerging and significant for future research on CMNP.

The top ten cited papers are summarized in Table 4, all of which were published in Q1 journals. Notably, the second most-cited paper has the highest impact factor (IF = 50.5). The most highly cited article is also the pioneering publication in this field, which demonstrated that coating biodegradable polymeric nanoparticles with natural erythrocyte membranes is an effective strategy for long-circulating cargo delivery [10]. The other highly cited references focused on cancer cell membranes [27,36–39], platelet membranes [29], neutrophil membranes [40], and hybrid membranes [32].

3.8 Keyword analysis

Figure 8a presents the network of co‐occurring keywords, highlighting hotspots for ongoing research in the field of CMNPs. The top five keywords, after excluding subject terms, are cancer (n = 117), photothermal therapy (PTT, n = 81), erythrocyte membranes (n = 52), photodynamic therapy (PDT, n = 52), and immunotherapy (n = 52). To analyze co-occurring keywords, 14 distinct clusters were generated using the log-likelihood ratio method. These clusters are identified as follows: #0 “drug delivery,” #1 “dendritic cells,” #2 “delivery,” #3 “homologous targeting,” #4 “cell membrane,” #5 “celastrol,” #6 “blood-brain barrier,” #7 “photothermal therapy,” #8 “cell membrane coating,” #9 “targeted therapy,” #10 “cancer treatment,” #11 “induction,” #12 “membrane coating,” #13 “targeted nanoparticles” (Figure 8b).

Figure 8

Analysis of keywords engaged in CMNP research: (a) keyword co-occurrence network and (b) keyword cluster analysis.

A timeline view of the keywords is presented in Figure 9a. Notably, #1 “dendritic cells” and #5 “celastrol” have emerged as hot topics in recent years, indicating a shift in research focus toward these areas. The top 24 keywords with the most powerful citation bursts are displayed in Figure 9b. The keywords with the strongest citation burst since 2011 are biomimetic nanoparticle (2011–2016), red blood cells (2011–2017), particles (2011–2019), and self (2011–2019). The most recent burst keyword is cell membrane coating (2021–2023). Additionally, the keyword polymeric nanoparticles has the highest burst strength of 8.07 from 2015 to 2019.

Figure 9

Analysis of keywords engaged in CMNP research. (a) Timeline view of the keywords and (b) the top 24 keywords with the strongest citation bursts.

3.9 Three-step process for CMNP preparation

The preparation of CMNPs involves a systematic three-step process, which is summarized in Figure 10. This process is critical for ensuring the proper integration of cell membranes with nanoparticle cores, thereby enhancing the functionality and stability of the resulting biomimetic nanomedicines. The first step involves selecting an appropriate cell membrane based on the intended application of the CMNPs. The extraction method is chosen according to the characteristics of the selected cell type. Chemical extraction methods and physical extraction methods are commonly applied. The second step focuses on preparing a nanoparticle core, which will be coated with the extracted cell membrane. The choice of nanoparticle carrier is crucial as it determines the physicochemical properties and the overall performance of the CMNPs. Common nanoparticle carriers include lipid-based, polymeric, and inorganic-based carriers. The third step is the integration of the extracted cell membrane with the nanoparticle core. This step ensures that the nanoparticles are effectively camouflaged with the cell membrane, retaining the biological functions and characteristics of the original cells. The methods, including mechanical extrusion, ultrasound, and microcurrent perforation, are frequently applied. Specific preparation methods and detailed procedures for selecting a selection of cell membranes and materials can be found in the reviews by Zhang et al. [7], Li et al. [41], and Kommineni et al. [9].

Figure 10

Generation and processing of CMNPs.

3.10 Recently published papers

To track the latest advancements in the field of CMNPs, we searched and analyzed the recently published literature in the first quarter of 2024. From January 1, 2024, to April 23, 2024, we retrieved a total of 59 papers. Among these, Tang et al. published a review on the application of cell membrane bionics in cancer phototherapy [42]. Tumor treatment continues to be a major focus of research [43–47]. In addition, research has explored the application of CMNP in the treatment of non-alcoholic fatty liver disease [48] and rheumatoid arthritis [49].

4.1 Global trends on CMNPs

The volume of scholarly publications concerning CMNPs increased significantly from 2011 to 2023, as illustrated in Figure 1. The proliferation of CMNPs globally was pronounced until 2014, following which point a notable surge occurred over the next 9 years. Therefore, it seems logical to assume that the field will reach its zenith zone in upcoming years. Analysis of publication output across countries/regions reveals China and the United States as prominent contributors, surpassing other countries/regions in productivity and are the most productive countries in the field. With the highest H-index along with the largest number of publications and citations, China emerges as a principal force in CMNP research, accounting for 80% of the productivity of among the top ten institutions. However, preeminent institutions and authors in this field are identified as the University of California System and Liangfang Zhang from the United States. Therefore, efforts are warranted in China to fortify institutional and authorial influence. In addition, this research gap underscores the imperative of reinforcing international cooperation and resource sharing. In terms of publications, ACS Nano, ACS Applied Materials Interfaces, and Advanced Functional Materials have been deemed the top three journals in the field, with ACS Nano leading in both publication count and H-index, while Advanced Materials excels in citations, average number of citations per paper, and impact factor.

Interdisciplinary collaboration in CMNPs is thriving presently, with researchers from materials science, biology, and medicine synergizing efforts to confront multifaceted challenges. This collaborative endeavor entails exchanging knowledge, expertise, and resources to innovate solutions potentially transformative for healthcare and biotechnology. However, avenues for enhancing future interdisciplinary collaboration in CMNP necessitate attention:

Enhanced communication: Improved communication channels are essential for fostering collaboration across disciplines. Clear communication of goals, methodologies, and findings can facilitate understanding and promote effective collaboration.

Interdisciplinary training: Providing interdisciplinary training programs can help researchers develop a deeper understanding of diverse fields and foster a collaborative mindset. This could involve joint workshops, seminars, or courses that expose researchers to different perspectives and methodologies.

Resource sharing: Facilitating the sharing of resources, such as equipment, databases, and experimental protocols, can streamline collaborative efforts and maximize efficiency. Establishing centralized repositories or platforms for resource sharing could benefit researchers across disciplines.

Incentivizing collaboration: Recognizing and rewarding interdisciplinary collaboration in academic settings can incentivize researchers to collaborate. Funding agencies, institutions, and academic journals can play a role in promoting and supporting interdisciplinary research initiatives.

4.2 Influential studies on CMNPs

An analysis of the top ten most cited publications, typically emblematic of pivotal studies in the field, elucidates significant advancements. The most highly cited article was also the first paper in this field, revealing the efficacy of coating biodegradable polymeric nanoparticles with natural erythrocyte membranes for long-circulating cargo delivery [10]. A substantial focus lies on cancer CMNPs, attracting significant interest from five other studies over the top ten most cited studies. Zhang and colleagues [27] observed enhanced delivery of tumor-associated antigens and immune adjuvants to special antigen-presenting cells via nanoparticles enveloped in cancer cell membranes, stimulating anti-cancer immune responses. Cai et al. [36] reported a highly effective nanoparticle encapsulated with a cancer cell membrane. This oncocyte homologous nanoparticle served as a biomimetic nanoplatform for cancer-targeted imaging and PTT. Furthermore, noteworthy contributions from Zhang et al. [39] include the fabrication of biodegradable mesoporous copper/manganese silicate nanospheres encoded by cancer cell membranes, demonstrating potent therapeutic effects via combined photodynamic/chemodynamic therapy. Liu et al. [38] proposed a strategy for constructing cancer vaccines by encapsulating immune adjuvant nanoparticles with mannose-modified cancer cell membranes. Similarly, Li et al. [37] reported a biomimetic drug delivery system that utilized 4T1 breast cancer cell membranes in conjunction with paclitaxel-loaded polymer nanoparticles. This innovative system effectively suppressed the growth and lung metastasis of breast cancer cells. Another significant study detailed the synthesis of polymeric nanoparticles encapsulated in the plasma membrane of human platelets [29]. These nanoparticles demonstrated decreased reduced uptake by macrophage-like cells and did not trigger complement activation in autologous human plasma. Furthermore, nanoparticles encapsulated within neutrophil membranes exhibited notable therapeutic effects by ameliorating joint damage and suppressing overall arthritis symptoms [40]. Heterogeneous cell membranes have also garnered extensive attention. Zhang et al. demonstrated dual membrane-coated nanoparticles created from fused erythrocyte and platelet membranes [32], further expanding the versatility and potential applications of CMNPs.

4.3 Hotspots and frontiers of CMNPs

Reference co-citations analysis and keyword analysis offer valuable insights into prevailing trends and frontiers in CMNP research. Key focus areas in cell membrane selection encompass macrophage membranes, neural cell membranes, and erythrocyte membranes, while therapeutic applications predominantly center on tumors and pulmonary inflammation. Noteworthy technological amalgamations include the integration of PTT and PDT.

Hot research on cell membranes : Since 2016, researchers have explored macrophage membrane-camouflaged Au nanoshells [50], subsequently applying them in the treatment of tumors [51,52], hepatic ischemia-reperfusion injury [53], acute pancreatitis [54], and atherosclerosis [55]. Macrophage mimetic nanoplatforms can imitate macrophages, demonstrating inflammatory tropism and the ability to neutralize pro-inflammatory cytokines and toxins through membrane surface receptors. Consequently, macrophage biomimetic nanoplatforms exhibit substantial therapeutic effects and hold excellent potential for utilization in inflammation-related diseases [56]. Similar to cancer cell membranes, nanoparticles encapsulated in neuronal cell membranes can serve as active targeting agents [57,58]. The erythrocyte membrane is one of the most extensively studied cell membranes. Erythrocytes, being the most abundant circulating cells in the blood, are widely utilized in drug delivery systems due to their biocompatibility, biodegradability, and long-circulating half-life [59]. In addition, hybrid membranes formed by combining erythrocyte membranes with other cellular membranes have garnered significant attention [60–62]. However, the current efficiency of synthesizing nanoparticles encapsulating cell membranes is relatively low, and there is still a deficiency in appropriate technologies for the mass production of CMNPs. To address these challenges, continuous efforts must be made to optimize the preparation process of CMNPs, improving encapsulation efficiency and scaling up production.

Hot research in diseases: Cancer remains the second leading cause of human mortality, maintaining its status as a primary focus in global biomedical research and practice. The advent of CMNP technology has introduced innovative modification and camouflage strategies for developing highly specific nanoparticles with low immunogenicity. Currently, CMNPs have been employed effectively in the treatment of various tumors, showcasing favorable outcomes [41]. Additionally, tumor microarrays, which have been developed recently to investigate tumor progression, may become a hotspot for future research on CMNPs in terms of tumor treatment [63]. Pulmonary inflammation is a commonly reported clinical tissue. Effective control of inflammation is essential to postpone the progression of inevitable and fatal pulmonary degeneration. Mesenchymal stem cell hybridized nanocarriers have shown potential in enabling highly target-specific inflammatory intervention in pulmonary [64,65]. This suggests a promising avenue for further research into the therapeutic effects of other cell membrane bionic systems in treating pulmonary inflammation.

Hot research in technology combinations: In 2014, a study demonstrated that combining PTT with erythrocyte membrane-coated nanoparticles resulted in a synergistic therapeutic effect, selectively ablating cancer cells in the radiation-exposed areas [66]. This finding has since spurred extensive research into the use of cell membrane-encapsulated nanoparticles in conjunction with PTT [61,67,68]. PTT induces cell death through a photothermal reaction, wherein light of a specific wavelength raises the cellular temperature. PDT involves photosensitizers that generate a significant amount of reactive oxygen species when exposed to specific light wavelengths, effectively inducing cell death [69–71]. This method has been integrated with CMNPs to enhance therapeutic efficacy. Compared to PDT and PTT, sonodynamic therapy (SDT) demonstrates a superior ability to penetrate deep tissue and is well tolerated by patients. SDT uses ultrasound waves to activate sonosensitizers, generating ROS and inducing cell death in targeted tissues. Further research should explore the potential benefits of combining CMNPs with SDT to leverage the deep tissue reach of SDT with the targeting capabilities of CMNPs.

4.4 Potential clinical transformation value

Despite promising developments in CMNP technology, there remains a lack of clinical application data for CMNPs. However, an ongoing clinical comparative study aims to evaluate the effectiveness of platelet-rich fibrin membrane-loaded hydroxyapatite nanoparticles versus tricalcium phosphate nanoparticles in treating gingival recession [72]. This study may provide valuable insights into the clinical potential of CMNPs. Based on anticipated outcomes, nanomaterials coated with erythrocyte membranes – with relatively mature synthesis technology – could soon be translated into clinical applications. Additionally, macrophage membrane-coated nanomaterials hold significant promise for treating inflammation-related diseases. Furthermore, the combination of CMNPs with other therapeutic techniques warrants further validation through clinical studies. However, the following concerns must be considered before clinical applications. First, overcoming the efficiency of cell membrane separation and identifying nanoparticles with optimal characteristics for human utilization is crucial. Second, the significant heterogeneity between human diseases and basic experimental models needs careful consideration. Developing a comprehensive evaluation system to assess the in vivo efficacy and safety of CMNPs within biosystems is imperative. Finally, it is essential to determine whether CMNP products could induce acute or chronic adverse reactions in humans and whether these reactions stem from the drug itself or the nanoparticle carriers.

4.5 Strengths and limitations

This study represents the first thorough analysis of the trends and hotspots of CMNPs based on the literature published from 2011 to 2023 through a bibliometric approach and scoping review. Nevertheless, the current study has some limitations. First, all bibliographic data were retrieved exclusively from the WoSCC. Consequently, some relevant papers may have been missed. Second, converting data formats to merge papers from multiple databases could impact the accuracy of results due to the differing attributes and indexing standards of each database. Third, this study only included articles published in English, which may result in language bias. Finally, bibliometric analysis typically relies on metadata such as titles, abstracts, and keywords. However, not all articles provide complete or detailed abstract information, potentially leading to deviations in the understanding of the research content. Despite these limitations, the WoSCC database contains many of the world’s most prestigious and influential academic journals, making it a highly representative source for this type of analysis. Therefore, we believe that existing findings can effectively depict the global status and trends in the field of CMNP research.