Abstract
Over the past two decades, silica-based nanobiomaterials (SNs) have emerged as a promising frontier in regenerative medicine, garnering substantial interest for their potential applications. Despite this growing interest, a notable lack of comprehensive and dynamic analyses remains, examining the evolution, development trends, research hotspots, and prospects of SNs in this field. To address this gap, we systematically analyzed 853 research articles published between 2006 and 2025 in the Science Citation Index Expanded (Web of Science Core Collection). Using bibliometric tools—CiteSpace, VOSviewer, and Biblioshiny—we generated data-driven visualizations to elucidate publication trends, contributions by countries/regions and institutions, journal distributions, research categories, thematic focuses, reference networks, and keyword dynamics. Our findings reveal a rapid acceleration in research output. While China leads in academic output volume, the United States maintains a significant advantage in average citation frequency, highlighting disparities in research impact. Current research hotspots include drug delivery systems, antimicrobial activity, bone regeneration, and wound healing. Keyword burst analysis identifies emerging frontiers such as mesoporous bioactive glass nanoparticles, wound healing, and zinc ion dopants. This study not only maps the trajectory of SNs in regenerative medicine but also discusses critical challenges and future directions, offering valuable insights for advancing the field.
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Introduction
Regenerative medicine is an interdisciplinary field at the forefront of science, dedicated to repairing damaged tissues and restoring normal physiological functions through innovative technologies1. In recent years, nanomaterials have gained significant attention for their potential in diverse regenerative applications, including bone tissue engineering, drug delivery, and wound healing. These materials are categorized by their structural forms, such as nanoparticles, nanofibers, nanotubes, and nanosheets2. Nanobiomaterials offer unique advantages, including high drug-loading efficiency due to their large surface area, the ability to deliver drugs to specific tissues through surface functionalization, and the capacity to mimic the natural extracellular matrix, thereby enhancing cell adhesion, proliferation, and differentiation3,4. However, tissue regeneration is an intricate and tightly regulated process that involves complex interactions among multiple cell types, signaling pathways, extracellular matrix components, and precise timing5. While traditional nanobiomaterials have demonstrated certain benefits, they often fail to meet the multifaceted demands of tissue regeneration. Key limitations include inadequate mechanical strength6, poor osseointegration, limited biocompatibility7, and insufficient support for angiogenesis8. To overcome these challenges, developing advanced materials with improved properties is essential for advancing the field of regenerative medicine.
Silica-based nanobiomaterials (SNs) are nanoscale biomaterials composed of silicon, an abundant element and an essential trace nutrient for humans9. In recent years, SNs have emerged as a key player in regenerative medicine due to their exceptional biocompatibility, bioactivity, and structural versatility (Fig. 1)10. Among the most widely used SNs are mesoporous silica nanoparticles (MSNs) and bioactive glass nanoparticles (BG-NPs), which are prized for their high surface area, large pore volume, tunable pore sizes, and modifiable surfaces. These properties make them ideal candidates for targeted drug delivery and as components in scaffold materials for controlled drug release11,12. By functionalizing these nanoparticles—such as through doping with metal ions—SNs can be engineered to perform specialized roles, including promoting hemostasis, antimicrobial activity, angiogenesis13, and osteogenesis14. Additionally, the mechanical properties of SNs make them effective as bioactive fillers, enhancing the mechanical strength and overall performance of scaffold materials15. Over the past two decades, advancements in synthesis techniques have further improved the properties of SNs, expanding their applications in regenerative treatments such as bone regeneration, wound healing, and periodontal regeneration, among others (Fig. 1).
The development is divided into three phases: Phase 1 (2012–2013): Focused on in vitro evaluation of the physicochemical and biological properties of SNs. Studies examined how incorporating SNs influenced scaffold properties, including mechanical strength, degradation rate, swelling behavior, protein adsorption, and cytocompatibility118,119; Phase 2 (2014–2018): Emphasized the multi-functionalization of SNs and their repair effects in in vivo models. Strategies such as drug and growth factor loading, metal ion doping, and functional group modification enabled SNs to promote cell proliferation, differentiation, angiogenesis, tissue adhesion, and antimicrobial activity110,120,121,122,123. A landmark study by Bari, Alessandra in 2017 explored mesoporous bioactive glass nanoparticles (MBGNPs) as multifunctional agents for bone regeneration110; Phase 3 (2019–2025): Advances in sequential therapy and clinical translation of SNs. Recent designs focus on mimicking natural bone healing processes and implementing sequential drug release strategies73,126. SNs’ injectability, temperature sensitivity, and ability to function without growth factors or cells enhance their cost-effectiveness and ease of clinical use, accelerating their translation into clinical applications86,124
The rapid growth in publications and the expansion of research in this field have made it increasingly difficult to pinpoint key trends and research hotspots. While existing reviews have explored the progress of SNs in terms of fabrication, design strategies, and applications10,16, there is still a lack of systematic research and comprehensive summaries of development trends, research hotspots, and the latest advancements. To address this gap, local literature datasets can be established using literature databases, enabling the analysis of article-related information such as titles, keywords, and citation data17. Visualization tools further enhance this process by generating detailed graphs that facilitate the identification of development trends and emerging research hotspots within specific fields. For instance, CiteSpace software offers rich maps and interactive features, allowing for in-depth exploration of node information. Similarly, the Bibliometrix R package provides a powerful platform for extracting and analyzing data on publication sources, authors, citations, and keywords. Additionally, VOSviewer can be used to create clear and structured collaboration networks, offering valuable insights into research dynamics.
This paper comprises three parts: the first part presents statistical data and visualization analyses based on the literature dataset, aiming to provide quantitative and qualitative insights into research trends and hotspots of SNs in regenerative medicine. It also enhances the understanding of the research development process; In the second part, research hotspots are primarily discussed through articles from the past three years, enabling researchers to grasp the latest field progress quickly. Finally, in the third part, we envision future research trends and propose key issues to be addressed based on the current state of research.
Materials and methods
Data collection
A comprehensive search was conducted in the Web of Science Core Collection (WoSCC) on January 18, 2025 (Supplementary Fig. 1). Using the Web of Science (WoS) interface, the search was filtered based on predefined inclusion criteria, resulting in an initial pool of 3772 publications. The inclusion criteria were: (1) articles written in English; (2) publication dates between 2006 and 2025; and (3) document type limited to “article”. Three authors collaboratively screened the 3772 articles, excluding 2919 entries that did not meet the criteria. This process yielded a final dataset of 853 publications, which were exported to create a local literature dataset. All subsequent visual analyses were based on this refined dataset. The excluded publications were removed for the following reasons: (1) articles misclassified as “articles” in WoS but were actually “reviews”; (2) publications unrelated to regenerative medicine; (3) studies focused on bioactive glass nanoparticle (BG-NP) applications in dental adhesives, caries prevention/treatment, and pulp capping; (4) research on tumor therapy; and (5) publications with abbreviations similar to MSN (e.g., muscle sympathetic nerve activity, MSNA). The content of the 853 included articles was exported as “Full Record and Cited References” to generate literature datasets in various formats. The tools and platforms used for analysis included the “Bibliometrix” R package, the online analysis platform at https://bibliometric.com/, CiteSpace (version 6.4.R1 advanced), VOSviewer (version 1.6.19), Origin (2022), and Tableau.
Data-driven visual analysis
The included publications were exported as literature datasets in multiple formats, each tailored for specific analyses. The primary data types extracted included titles, abstracts, keywords, publication years, journals, countries, institutions, authors, and references. (1) Bibtex Format: This format was used in Biblioshiny to extract data on publication volumes and impact metrics. Histograms were generated in Origin to visualize publication counts and citation frequencies. Additionally, Tableau software was employed to create a world map showcasing the distribution of publications by country. (2) Plain Text File Format: This format supported the creation of collaborative network maps, reference analyses, and keyword analyses. VOSviewer was used to map institutional and author collaboration networks, while CiteSpace facilitated burst analysis, co-occurrence mapping, and clustering. (3) Tab-Delimited Format: This format was utilized on the https://bibliometric.com/ online analytics platform to generate a country collaboration network map (Supplementary Fig. 2).
Results
Temporal evolution and geographical patterns of research productivity
The analysis of article publications reveals trends in the number of publications by country and the cumulative output from 2006 to 2025. Over the past two decades, research on SNs has grown rapidly, with 59.9% of the total publications produced in the last five years (Fig. 2a). The annual number of global publications increased from 1 in 2006 to 103 in 2024, reflecting an average yearly growth rate of 26.9% and an overall acceleration in research output. Figure 2a also presents a stacked graph of annual publications for the top five countries by total output. China leads with 388 publications, accounting for 32.7% of the total, followed by Germany and Iran. Figure 2b illustrates the geographical distribution of research activity, highlighting that the majority of researchers are concentrated in Asia and Europe. Figure 2c lists the top 5 institutions by publication volume and their centrality scores. The University of Erlangen-Nuremberg, Shanghai Jiao Tong University, and the Chinese Academy of Sciences rank as the top three institutions in terms of publication output. Figure 2d displays the publication volume of the top 10 journals alongside their impact factors. The leading journals are Acta Biomaterialia, ACS Applied Materials & Interfaces, and Journal of Materials Chemistry B. Collectively, these results highlight the primary institutions and journals driving research in this field, with China emerging as the leading contributor to the recent surge in global publication volume in SNs-related research.
a Stacked bar charts showing the annual number of publications by country (2006–2025) and a line graph depicting cumulative publication growth over the same period. b A world map illustrating the geographical distribution of publications by country. c The top 5 institutions ranked by publication volume, along with their centrality scores. d The top 10 journals ranked by publication volume, accompanied by their impact factors
The multidimensional analysis of academic impact
To assess the impact of individual countries, we analyzed 853 publications from 53 countries. This impact-related analysis provides insights into each country’s contribution and significance in the field. Figure 3a highlights the top 10 countries by total citation frequency and their average citation frequency per article. While China leads in total citations, its average citation frequency per article is relatively low at 20. In contrast, the United States has the highest average citation frequency at 52, reflecting the influential nature of its publications.
a Top 10 countries ranked by total citations, along with their average citation count per publication. b Top 10 authors ranked by total citations, along with their average citation count per publication
For author impact analysis, Fig. 3b displays the total citation frequency and average citations per article for the top 10 authors. Kim, Hae-Won has the highest total citation frequency (1432), while Nair, S. V. has the highest average citations per article (208). Notably, Boccaccini, Aldo R., Kim, Hae-Won, and El-Fiqi, Ahmed each have total citation frequencies exceeding 1000. It is worth noting that authors with higher publication counts are typically corresponding authors.
In terms of journal impact analysis (Table 1), Acta Biomaterialia ranks first in both the number of publications (37) and total citations (2504). Meanwhile, Bioactive Materials has the highest impact factor (18.0). Collectively, these findings summarize the impact metrics of countries, authors, and journals in this field. They highlight the influential role of U.S. publications, while suggesting room for improvement in the quality of publications from China.
The morphology of scholarly synergy networks
Regarding international collaboration, the network diagram in Fig. 4a serves as a valuable resource for researchers exploring global partnerships. The United States and China stand out as the most frequent collaborators among all countries.
a Country collaboration network: The size of each colored block corresponds to the number of articles published by that country. The connecting lines between blocks indicate collaborative relationships, with line thickness reflecting the intensity of collaboration. b Institutional collaboration network: Displays partnerships among institutions, with node size representing the number of articles published and line thickness indicating the strength of collaboration. c Author collaboration network: Node size represents the number of articles published by each author, while line thickness shows the strength of collaboration. Nodes are color-coded to distinguish different research clusters
Figure 4b highlights institutional collaboration, revealing a strong network among Shanghai Jiao Tong University, Fudan University, Donghua University, and the Chinese Academy of Sciences within China. Additionally, the closest international institutional partnership is observed between the National Research Centre (Egypt) and Dankook University.
In terms of author collaboration, Fig. 4c shows two distinct collaborative networks, each centered around Boccaccini Aldo R and El-Fiqi A, respectively. These findings suggest that academic collaborations at the country and institutional levels are diverse and robust, while collaborations among authors tend to form around independent research teams.
Knowledge foundations and intellectual structure
References with the highest citation frequency
Early high-citation references often form the theoretical foundation for later research. To better understand the development of the field, we conducted a comprehensive analysis of references cited across 853 publications. The local citation score measures how often a specific reference is cited within the dataset, helping to identify key early literature that has significantly influenced the field.
Among the top 25 references ranked by local citation score, eight are review articles, and two are research articles (Supplementary Table 1). The most frequently cited reference is the 2006 article titled “How useful is SBF in predicting in vivo bone bioactivity?”18, which has been cited 160 times within the dataset. This highlights its pivotal role in shaping subsequent research.
Reference co-citation network and cluster analysis
To trace the evolution of this field and identify key milestone literature, a co-citation network and clustering diagram of references was constructed (Fig. 5). Clusters are labeled sequentially starting from index #0, ordered by the number of references they contain, from largest to smallest. The nodes and clusters are arranged chronologically from left to right, spanning publications from 2006 to 2025. As shown in Fig. 5, references with high citation burst strength are concentrated in three clusters: Cluster #0 (bioactive glass nanoparticles): Focuses on early studies (2013 and earlier) exploring synthesis techniques, cytotoxicity, and structural control of micro-nano scale bioactive glass19,20, These studies laid the groundwork for the application of BG-NP in bone tissue engineering. Cluster #1 (mesoporous bioactive nanocarriers): Highlights advancements in synthesis methods, such as the “sol-gel” process, which improved the structural controllability of BG-NP and expanded its applications in regenerative medicine, including periodontal tissue regeneration and wound healing21. Cluster #2 (synergistic effect): Emphasizes recent research on the role of SNs in tissue regeneration through the synergistic delivery of metal ions, growth factors, antibiotics, or other therapeutic agents22,23. Additionally, Cluster #5 (mesoporous bioactive glass nanoparticles) reflects the growing interest in combining various bioactive ions to enhance bioactivity and optimize tissue regeneration capabilities24,25. These findings demonstrate a clear shift in research focus over time: early studies were primarily concerned with the synthesis and structural control of SNs, while later research has increasingly explored their applications in tissue engineering and regenerative medicine.
The clustering labels in the co-citation network were generated using the LLR (Log-Likelihood Ratio) algorithm in CiteSpace, based on the titles of the cited publications. The network’s modularity (Q = 0.8019, Q > 0.3) confirms that the cluster structure is statistically significant, while the weighted mean silhouette value (S = 0.9039, S > 0.7) indicates a high level of confidence in the clustering results. Nodes represent individual references cited by the publications. Node colors correspond to the years in which the references were cited, with red indicating more recent literature and green representing older literature. Red-highlighted nodes denote references with high citation burst strength, meaning they were frequently cited during a specific period. Connecting lines between nodes indicate that the two references were cited together in the same article. Color blocks group references that belong to the same topic or cluster. This visualization provides a clear overview of the field’s intellectual structure, highlighting key themes, influential references, and their temporal evolution
Keyword analysis
Temporal-spatial evolution and distribution of keywords
To identify past research hotspots and key turning points, we analyzed the distribution of keywords based on their first appearance over time (Fig. 6a). The top 10 most frequently occurring keywords are: bioactive glass, scaffolds, in vitro, mesoporous silica nanoparticles, nanoparticles, delivery, drug delivery, differentiation, bone, and bone regeneration. This analysis helps reveal the evolution of research focus and emerging trends in the field.
a Keyword co-occurrence time zone diagram: The size of each node reflects the frequency of a keyword’s occurrence, while its position along the timeline indicates the first year the keyword appeared in the dataset. b Top 20 keywords by burst strength, Year: The earliest year the keyword appeared in the dataset; Strength: The intensity of the citation burst for the keyword; Begin and End: The start and end years, respectively, of the period during which the keyword experienced a significant surge in citation frequency. This visualization highlights the temporal evolution of research hotspots and identifies keywords that have driven significant interest over time
Emergent research fronts: keyword burst dynamics
Analyzing keyword bursts provides insights into research hotspots over time, but identifying enduring research trends requires combining keyword clustering maps and reference co-citation maps. To this end, we extracted the top 20 keywords with the highest burst strength from both Author Keywords and Keywords Plus in the selected articles (Fig. 6b). Past hotspots: Keywords like hydroxyapatite, bone, stem cell, and drug delivery have historically attracted significant attention. For instance, hydroxyapatite was one of the earliest keywords to show a citation burst. This is because hydroxyapatite forms on the surface of BG-NP scaffolds after immersion in simulated body fluids, indicating their bioactivity and osseointegration potential26. Recent and ongoing hotspots: Keywords that emerged as prominent in the past five years and remain relevant through 2025 include mesoporous bioactive glass nanoparticle, sol-gel, mesoporous silica, wound healing, mechanisms, and zinc. Among these, drug delivery and wound healing exhibit the highest burst intensity, highlighting them as past or current research hotspots. The analysis in Fig. 6b reveals that research on mesoporous bioactive glass nanoparticles (MBGNP) gained significant traction starting in 2021 and continues to be widely cited through 2025, solidifying its status as a new and enduring research hotspot.
Keyword cluster timeline analysis
A keyword clustering timeline diagram (Fig. 7) was developed to identify the most prominent research topics in the field by grouping keywords related to the same themes. The six primary clusters identified are: wound healing, drug delivery, bone regeneration, mesoporous silica nanoparticles, antibacterial activity, and controlled release. The timeline analysis of these keyword clusters reveals six major research themes and their evolutionary trends from 2006 to 2025. The network structure exhibits high modularity, and the clustering quality is strong, offering valuable insights into the field’s development and guiding future research directions.
This visualization, generated using CiteSpace, displays the keyword clustering results. The network’s modularity (Q = 0.654, Q > 0.3) confirms that the cluster structure is statistically significant, while the weighted mean silhouette value (S = 0.8779, S > 0.7) indicates a high level of confidence in the clustering. Node size represents the frequency of a keyword’s occurrence. Node position indicates the year the keyword first appeared in the dataset. Cluster labels, shown on the right side of the diagram, identify the main thematic groups. This map provides a clear overview of the evolution of research themes over time, highlighting key trends and their development
As new studies rapidly emerge, accurately and objectively identifying leading research hotspots has become increasingly complex. Keywords in articles typically reflect core research themes, making keyword analysis a valuable tool for pinpointing current research trends. By conducting co-occurrence, burst, and cluster analyses of keywords, we identified four key research hotspots: drug delivery, antibacterial activity, bone regeneration, and wound healing. Additionally, we uncovered one significant future development trend: MBGNP. These findings provide a clear framework for understanding the field’s current focus and future direction.
Discussion
To gain a comprehensive understanding of research trends and hotspots related to SNs in regenerative medicine, a data-driven visualization analysis was conducted using a literature dataset, offering a dynamic perspective on the field’s evolution. Publication Trends: Over the past five years, the volume of publications has shown explosive growth, reflecting increasing interest in this area (Fig. 2). Research Focus Shift: Early studies primarily focused on the synthesis processes of SNs, but over time, the emphasis has shifted toward their applications in regenerative medicine (Fig. 5). Emerging Keywords: In the last five years, keywords such as “electrophoretic deposition,” “sol-gel,” “mesoporous bioactive glass nanoparticle,” “mechanism,” “drug,” and “activation” have gained significant attention and remain prominent through 2023 (Fig. 6b). Research Hotspots: Keyword clustering analysis (Fig. 7) identified four major research hotspots: “drug delivery,” “antibacterial activity,” “bone regeneration,” and “wound healing.” The following sections will explore global research trends, current hotspots, future developments, and key unresolved challenges.
Global trends of SNs in regenerative medicine
Research on SNs in regenerative medicine is progressing rapidly, making it essential for researchers to stay informed about emerging hotspots and frontiers to maintain a competitive edge in the field. Country-Level Contributions: As illustrated in Fig. 2a and Fig. 3a, China leads in both publication volume and total citation frequency. However, it has the lowest average citations per article, likely due to the recent surge in publications from China, as newer articles typically accumulate fewer citations over time. In contrast, the United States has the highest average citations per article among the top 10 countries, reflecting the significant influence of American researchers in advancing this field. Journal-Level Impact: Among the top 15 journals by total citations (Table 1), Bioactive Materials stands out with the highest impact factor. Articles in this journal emphasize the critical role of biomaterials in addressing real-world clinical challenges, underscoring its importance in the field. Collaboration Networks: A comparison of Fig. 4b (institutional collaboration) and Fig. 4c (author collaboration) reveals that institutional collaborations are more extensive, while author collaborations are relatively isolated. This suggests that author partnerships may be limited by research focus, geographic proximity, or affiliation with the same team, resulting in smaller, more stable networks. The University of Erlangen-Nuremberg exhibits the highest total connection strength, highlighting its extensive collaborations with other institutions and its considerable influence in the field. Research Evolution and Emerging Trends: The co-citation network and clustering diagram (Fig. 5) indicate that early advancements in synthesis processes laid the theoretical foundation for the subsequent surge in publications, expanding the applications of SNs in regenerative medicine. Among keywords with high burst strength in the past five years (Fig. 6b), “MBGNP” has gained significant attention as nanocarriers for co-delivering therapeutic ions and molecules to treat hard-tissue injuries24. The “sol-gel” process, widely used to synthesize metal ion-doped MBGNP and MSNs, is closely linked to the growing interest in MBGNP15,27,28. In summary, while China dominates in publication volume, the quality of its articles, as measured by average citations, still requires improvement. Articles involving American authors, publications in Bioactive Materials, and research from the University of Erlangen-Nuremberg demonstrate significant impact, reflecting their leadership in advancing the field. This analysis highlights the dynamic evolution of SNs research in regenerative medicine, emphasizing key contributors, emerging trends, and areas for future growth. By understanding these patterns, researchers can better navigate the field and contribute to its continued progress.
Research hotspots of SNs in regenerative medicine
The following discussion focuses on the key research hotspots identified through keyword analysis: drug delivery, antibacterial activity, bone regeneration, and wound healing (Fig. 7). These themes are visually summarized in Fig. 8, which schematically illustrates the primary research hotspots of SNs in regenerative medicine and their main therapeutic strategies. This framework provides a clear overview of the field’s current focus and its potential applications.
(1) Drug Delivery: Surface modification of SNs enhances drug loading and delivery efficiency, enabling controlled release and targeted delivery of therapeutic agents to specific sites. (2) Antibacterial Applications in Tissue Engineering: SNs are primarily loaded with antimicrobial drugs to achieve antibacterial effects. Collaborative antimicrobial platforms enhance their efficacy against bacterial resistance and compromised immune function. By incorporating SNs into scaffolds and dressings, they can simultaneously combat infection and promote tissue regeneration. (3) Bone Regeneration: SNs support bone regeneration through four key strategies, including, Loading therapeutic agents (e.g., drugs, cytokines, metal ions, and genes) to promote osteogenic cell differentiation or inhibit osteoclast activity; Stimulating bone angiogenesis to provide nutritional support for new bone formation; Modulating the bone immune microenvironment to promote cytokine secretion that supports osteogenesis or suppresses osteoclasts; Regulating the nerve microenvironment to enhance bone regeneration further. (4) Wound Healing: SNs are utilized across all critical phases of wound healing, including hemostasis, inflammatory response, cell proliferation and differentiation, and tissue remodeling. This schematic highlights the diverse therapeutic applications of SNs in regenerative medicine, showcasing their potential to address complex clinical challenges
Drug delivery
Due to their strong biocompatibility and exceptional drug-loading capabilities, SNs are extensively used in regenerative medicine as drug delivery systems. Among these, MSNs and MBGNPs are particularly favored as drug carriers due to their adjustable structures, large surface areas, and high pore volumes29. Chemical modifications of SNs can further enhance their functionality by improving drug delivery efficiency, enabling controlled drug release, and increasing drug concentrations in targeted tissues, making them versatile tools in regenerative medicine3 (Table 2).
In regenerative medicine, SNs have significantly enhanced drug loading and delivery capabilities. These advancements can be summarized as follows: (1) Functionalization with phosphate, carboxyl, or sulfhydryl groups improves electrostatic adsorption, thereby enhancing drug loading capacities30. (2) Drug loading efficiency is improved through modification using amino and palmitoyl chlorides or through combination with a phospholipid bilayer coating31,32,33. (3) Grafting of anti-biofouling materials (e.g., polyhydrophilic polymers) improves biocompatibility and prolongs blood circulation time30,34. These surface modifications, including functional groups and polymer coatings, effectively enhance drug adsorption, increase drug-carrying efficiency, optimize drug release kinetics, and improve biocompatibility, making SNs highly versatile and effective in drug delivery systems for regenerative medicine.
Responsive drug delivery systems enable stimuli-triggered drug release. These systems provide benefits such as “zero premature release”35, higher local drug concentration, and minimized drug uptake by non-target cells. Drug release in acid-base environments can be achieved by encapsulating SNs with substances such as chitosan or calcium phosphate36,37 (Fig. 9), which dissolve rapidly at a specific pH, and by loading drug precursors that react with acids or bases. Conditions like spinal cord injury and Alzheimer’s disease produce excessive reactive oxygen species (ROS)35,38. ROS-responsive MSN, containing diselenide bonds and polyethyleneimine, loads therapeutic siRNA and releases it when ROS levels trigger the oxidative cleavage of diselenide bonds38. Unlike passive release in other responsive systems, drug release can be actively regulated by external stimuli such as light and heat. Hemin, a photothermally responsive switch loaded into hollow mesoporous silica pores, heats up under near-infrared light and dissolves, facilitating drug release from the carrier39 (Fig. 9c). Various MSN pore “gatekeepers,” including polymers, metal nanoparticles, nanosheets, host-guest assemblies, and biomacromolecules, match different stimuli with specific gating mechanisms40. Beyond pH, ROS, light, and heat, MSN-responsive delivery systems for cancer therapy use stimuli such as enzyme activation (e.g., matrix metalloproteinases), magnetic stimulation, and ultrasound, offering additional design options30.
a pH-responsive drug delivery systems: MSN loaded with drugs and encapsulated by chitosan or calcium phosphate are internalized by cells. Acidic lysosomal conditions open the pores and trigger drug release36,37. b ROS-responsive drug delivery system: MSN is modified with 3-carboxyphenylboronic acid, forming stable cyclic esters with saccharide diols. IgG forms boronate ester bonds with the cyclic ester, closing the MSN pore. ROS degrades these boronate ester bonds, initiating cargo release35. c Photothermally responsive drug delivery systems: Hollow MSN loaded with cargo are coated with hemin, sealing the channels. Near-infrared light heats and dissolves the hemin, opening the channels to release the cargo. d Magnetically targeted drug delivery system: Consists of core-shell structured magnetic SNs and an external magnetic field42,43. e Ligand-mediated targeted drug delivery system: Utilizes cell-targeting ligands immobilized on the surface of nanoparticles44. f Cell membrane-targeted drug delivery system: Encapsulates SNs within specific cell membranes for preferential uptake and targeting to source cells46
In vivo, off-target drug accumulation and prolonged high-dose administration can lead to increased cytotoxicity and reduced therapeutic effectiveness41. Therefore, achieving targeted drug delivery and controlled release at specific sites is critical for successful treatment outcomes. Magnetic field-guided targeting incorporates an external magnetic field with magnetic SNs, enabling spatial localization of nanoparticles in vivo, thereby increasing local drug concentration (Fig. 9d)42,43. Ligand-mediated targeting drug delivery can also be targeted by immobilizing cell-targeting ligands on the surface of nanoparticles, such as monosaccharides, peptides, and antibodies. For example, coupling CD11b antibodies to MSN surfaces allows precise targeting and delivery of drugs to damaged cardiomyocytes44 (Fig. 9e). Another practical targeting approach involves loading MSN with growth factors or drugs that actively recruit target cells45. Furthermore, biomimetic construction strategies utilizing biological cell membranes encapsulated with SNs for drug-targeted delivery are gradually emerging. For instance, encapsulating MSN within pre-osteoblast (MC3T3-E1) cell membranes resulted in significant uptake of MSN by specific cells (source cells), reduced the uptake of MSN by other cell types, and exhibited preferential migration toward the pre-osteoblast source cells in an in vitro migration model46 (Fig. 9f). In vivo, targeted drug delivery can be achieved through various methods, including external magnetic fields, cellular ligands, biological cell membrane coatings, and cytokine loading.
Techniques such as functional group modification, biofilm encapsulation, metal ion or nanoparticle doping, and polymer and protein coatings have significantly enhanced the performance of drug delivery systems, particularly in terms of the loading capacity, controlled release, and targeted delivery of SNs47. Furthermore, developing high-performance and controllable-release drug delivery systems is crucial for enabling effective subsequent treatments.
The antibacterial application of SNs in tissue engineering
Bacterial infection of biomaterials in regenerative medicine applications can lead to treatment failure, including the occurrence of ischemia due to bacterial infection of orthopedic implants48, bacterial production of virulence factors that hinder wound healing49 and weak regeneration of infected dental pulp50. As a result, the antibacterial properties of biomaterials have become a key area of research, essential for successful clinical translation. SNs hold significant promise for application and clinical translation due to their high pore volume, specific surface area, and tunable physical structure29,51. The following section summarizes the research progress of SNs-based antibacterial strategies in regenerative medicine from three perspectives: delivering antimicrobial drugs, creating collaborative antibacterial platforms, and developing antibacterial dressings and scaffolds.
Antimicrobial drug delivery is one of the most commonly used antibacterial strategies. As drug carriers, SNs facilitate complete drug release within injured tissues, thereby achieving optimal antibacterial effects (Fig. 10a). For instance, the combined use of MSN with polymethyl methacrylate has been shown to enhance the release efficiency of gentamicin, and the diffusion network formed by this combination produces significant inhibitory effects against S. aureus and E. coli52. Furthermore, SNs loaded with antimicrobial drugs can be integrated into regenerative materials. For example, a mesh structure for bone adhesive, created by incorporating vancomycin-loaded MBGNP into an adhesive hydrogel, enables prolonged vancomycin release and ensures sustained antibacterial effects while promoting osteogenesis53.
a Antimicrobial drug delivery. SNs act as carriers, releasing antimicrobial drugs directly into injured tissues and enhancing antibacterial effects through diffusion. b Development of collaborative antibacterial platforms utilizing SNs loaded with antimicrobial drugs. Step I: Modify the surface of SNs with chemical groups or metal particles. Step II: Incorporate natural antibacterial ingredients into SNs. Step III: Dope SNs with antibacterial metal ions. c Fabrication of dressings and scaffolds with antibacterial properties. Step I: Incorporation of hyaluronic acid-coated MSN and β-cyclodextrin into the hydrogel system for long-lasting antibacterial effects in wound dressings59. Step II: Creation of bioactive scaffolds through three-dimensional (3D) printing using MSN mixed with hydrogel as ink to promote bacteriostasis and osteogenesis60
Bacterial resistance and weakened immunity can compromise the effectiveness of antimicrobial drugs. To enhance the antibacterial performance of SN-based materials, collaborative antibacterial platforms can be developed by utilizing SNs loaded with antimicrobial agents (Fig. 10b). Firstly, modifying the surface charge of SNs or depositing antibacterial particles can confer antibacterial properties. For example, MSN modified with amino groups interacts electrostatically with bacterial lipopolysaccharides, leading to the disruption of cell membranes31. Additionally, depositing gold nanoclusters on the surface of BG-NP disrupts bacterial cell structures and induces oxidative stress damage, resulting in strong antibacterial effects54. Secondly, incorporating natural antibacterial ingredients extracted from plants or animals into SNs can further enhance their antibacterial properties. For instance, the combination of essential oils, which dissolve the cell walls and membranes of Gram-negative bacteria, with gentamicin in MBGNP significantly inhibits the growth of E. coli55. Thirdly, adding antimicrobial metal ions can boost the antibacterial activity of SNs. Incorporating boron and zinc into BG-NP enhances these effects, as boron interferes with protein synthesis and enzyme activity in bacteria. In contrast, zinc disrupts glycolysis, damages cell membranes, and triggers free radical production in bacteria56. Furthermore, the combination of antimicrobial metal ions with antimicrobial drugs can maintain antibacterial performance while reducing the required drug concentration, thereby lowering the risk of drug resistance. For example, adding zinc to curcumin-loaded BG-NP increases the antibacterial efficacy, reducing the minimum inhibitory and bactericidal concentrations of curcumin against S. aureus57. However, it is crucial to avoid reductions in cell viability that may result from excessive amounts of antimicrobial metal ions58.
Although individual antibacterial components can be effective, they may also lead to side effects such as bacterial resistance, a narrow antimicrobial spectrum, and anaphylaxis. Various antibacterial components can be combined by developing collaborative antibacterial platforms using SNs, thereby improving antibacterial performance while reducing side effects.
Constructing antibacterial dressings and scaffolds using SNs allows for effective infection control while facilitating tissue regeneration (Fig. 10c). Effective wound dressings serve as barriers against external infections and promote healing. To achieve prolonged antibacterial effects, MSN coated with hyaluronic acid and β-cyclodextrin can be incorporated into a hydrogel system, enabling sustained drug release at the wound site and accelerating healing59. Furthermore, 3D printing technology enables the fabrication of customized antibacterial scaffolds that conform to the shape of damaged tissue. By loading lysozyme and gentamicin onto cerium and calcium-doped MSN and mixing them with hydrogels, a bio-ink suitable for 3D printing can be created. Following application, the metal ions promote bone healing and reconstruction, gentamicin imparts antibacterial properties, and lysozyme enhances the scaffold’s stability and resistance to degradation60. Thus, multifunctional composite dressings and scaffolds based on SNs possess enhanced antimicrobial properties that synergistically promote tissue regeneration while preventing external infections.
In summary, SNs demonstrate the ability to effectively deliver antimicrobial drugs, create collaborative antibacterial platforms, and fabricate antibacterial dressings and scaffolds. It is important to highlight that the development of bacterial resistance diminishes the efficacy of antimicrobial drugs, emphasizing the growing significance of developing novel antibacterial components, like antibacterial metal ions, for use in antimicrobial therapy.
Bone regeneration
The primary clinical causes of bone defects include osteoporosis, traumatic fractures, bone tissue inflammation, bone tumors, and systemic diseases. Bone tissue engineering and related approaches for promoting bone regeneration have emerged as crucial research areas in regenerative medicine. Bone tissue engineering is an interdisciplinary field that combines biology, engineering, and materials science to repair bone defects and facilitate bone regeneration. The main objectives of this approach are to regenerate bone tissue by inducing osteogenic differentiation of stem cells42, delivering therapeutic factors that stimulate bone formation (such as drugs, metal ions, and genes), and implanting bone scaffolds or replacement implants61,62,63. Despite significant progress in bone regeneration research due to advancements in materials and technology, with many materials exhibiting robust osteogenic activity both in vitro and in vivo, some biomaterials still have limitations, including low mechanical strength, inadequate biocompatibility, poor osteoconductivity, insufficient elasticity, and susceptibility to infection64. SNs offer potential solutions to these challenges. For example, MBGNP enhances the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), supporting in vivo bone regeneration15. Furthermore, using SNs as scaffold fillers can improve the mechanical strength and bioactivity of scaffolds15. The incorporation of BG-NP into scaffolds can further enhance in vivo osseointegration65. The three primary therapeutic strategies for bone regeneration are delivering agents that directly promote osteogenesis, enhancing bone angiogenesis, and modulating the bone immune microenvironment.
Direct delivery of therapeutic agents via SNs to enhance osteogenic differentiation is a pivotal therapeutic strategy in bone regeneration (Fig. 11a). The mesoporous structure of MSN has been utilized to deliver osteogenic drugs and cytokines66 while doping metal ions such as strontium, magnesium, or zinc62,67) into the particles has been employed to promote cell differentiation directly. Additionally, it is essential to inhibit osteoclast differentiation while promoting osteogenesis to minimize bone resorption, which is a critical aspect of achieving an “osteogenesis-osteoclast” closed-loop therapeutic management strategy. In drug therapy, MBGNP can deliver alendronate sodium68, whereas hollow mesoporous silica nanoparticles can deliver kaempferol69, which inhibits osteoclast differentiation. The molecular mechanism of the former remains unclear, while the latter inhibits osteoclast differentiation through the NF-κB pathway68,69. In the realm of gene therapy, hollow mesoporous silica nanoparticles can be loaded with gene-editing plasmids that knockout the Receptor activator of nuclear factor kappa-B (RANK), thereby inhibiting osteoclast differentiation by reducing the production of receptor activator of nuclear factor kappa-B ligand (RANKL)70. Furthermore, BG-NP has been shown to induce BMSCs to secrete extracellular vesicles enriched with long non-coding RNA NRON, which inhibits osteoclast differentiation71. Overall, the “osteogenesis-osteoclast” closed-loop management strategy represents a fundamental therapeutic approach in bone regeneration, involving the delivery of therapeutic agents that directly promote osteogenic differentiation while inhibiting osteoclast differentiation.
a SNs facilitate osteogenesis and inhibit bone resorption by delivering therapeutic factors that directly promote osteoblastic differentiation or inhibit osteoclast differentiation. b SNs promote bone angiogenesis73. c Regulation of the immune microenvironment: I. MSN-mediated delivery of miRNA-21a-5p promotes M2-type macrophage polarization, which secretes anti-inflammatory cytokines conducive to osteogenesis II. Sr-BG-Np regulates immune cells, reducing RANKL secretion and inhibiting bone resorption78. III. Therapeutic agents such as procyanidins, cerium ions, and metformin mitigate excessive ROS accumulation, which can induce osteoblast senescence and promote osteoclast differentiation and bone resorption, thereby fostering an immune microenvironment supportive of osteogenesis. d Neural microenvironment regulation: Delivering propranolol (PRN) suppresses β-adrenergic receptor activation on BMSCs, while calcitonin gene-related peptide released from the scaffold mimics neural innervation within the bone82
However, a major challenge in bone regeneration therapy is inadequate vascularization, which hinders the delivery of essential nutrients and oxygen to cells, ultimately leading to apoptosis72. To tackle this problem, dual-drug delivery using MSN has been employed to deliver bone-forming peptide-1 and dimethyloxalylglycine73. This approach chemically induces the production of vascular endothelial growth factor, synergistically promoting osteogenesis and angiogenesis (Fig. 11b). Furthermore, vascular endothelial growth factor can be immobilized on the surface of BG-NP by conjugating peptides, thus stimulating bone vascularization74.
In addition to directly regulating osteogenesis-related cells, bone regeneration can also be facilitated indirectly by modulating the bone immune microenvironment (Fig. 11c). The primary focus of bone immunomodulation is to activate immune cells, inhibit osteoclast differentiation, and eliminate excessive ROS, thereby fostering an immune microenvironment that is conducive to osteogenesis and indirectly promoting bone regeneration. With regard to immune cell activation, recent research has concentrated on promoting macrophage polarization toward the M2 phenotype75,76. Previous studies have demonstrated that M1 macrophages secrete pro-inflammatory cytokines, stimulating osteoclast differentiation. Conversely, M2 macrophages secrete anti-inflammatory cytokines that create a bone immune microenvironment favorable for bone regeneration77. Consequently, such a microenvironment promotes osteogenic cell differentiation and inhibits osteoclast differentiation75,76. To suppress osteoclast differentiation, BG-NP stimulates macrophages to secrete extracellular vesicles, which enhance the differentiation of Treg cells and inhibit the differentiation of Th17 cells78 (which secrete large amounts of RANKL), thereby impeding osteoclast differentiation. These extracellular vesicles induced by BG-NP can absorb significant quantities of RANK, functioning as competitive inhibitors for RANKL binding and inhibiting osteoclast differentiation78. Furthermore, in response to stimuli such as infection, trauma, and chronic disease, bone immune cells secrete inflammatory mediators that can generate excessive ROS and elicit inflammatory responses. Although moderate ROS levels are necessary for osteoblast function and bone regeneration, excessive ROS accumulation can impair osteoblast function and inhibit osteogenesis70,79. Moreover, accumulated ROS can induce osteoblast senescence and excessive RANKL secretion, activating osteoclast differentiation70,80. To mitigate the detrimental effects of excessive ROS and promote bone regeneration, composite nanoparticles with potent ROS scavenging abilities (such as HPB@RC-ALN70) can be developed, ROS-responsive drug delivery systems can be created79, and cerium ions can be incorporated81. Collectively, activating immune cells, inhibiting osteoclast differentiation, and reducing excess ROS support osteogenic differentiation while inhibiting osteoclast differentiation.
In addition to the previously mentioned points, modulation of the neural microenvironment presents a novel therapeutic approach for bone regeneration. Specific neuropeptides have been discovered to promote osteogenesis. However, post-traumatic stress disorder (PTSD) can lead to excessive activation of the sympathetic nervous system and an over-release of catecholamines, which negatively impact bone regeneration. To address this, delivering propranolol via MSNs blocks the binding of catecholamines to β-adrenergic receptors on BMSCs, thereby enhancing bone regeneration through the release of silicon ions and neuropeptides82 (Fig. 11d). This strategy lays a theoretical groundwork for future bone regeneration therapies targeting disorders characterized by sympathetic hyperactivation.
The dual regulation of osteogenesis and osteoclastogenesis, which involves promoting osteogenic differentiation and inhibiting bone resorption, is a fundamental and essential therapeutic approach in bone regeneration. Additionally, enhancing bone angiogenesis, modulating the bone immune microenvironment, and adjusting the neural microenvironment can complement core therapeutic strategies, promoting bone regeneration from multiple angles and leading to improved therapeutic outcomes.
Wound healing
Wound healing is a complex, multistage process that includes hemostasis, inflammation, cell proliferation, and tissue remodeling. In the early stages of wound healing, immediately following tissue damage, hemostasis and inflammation occur. The blood coagulation cascade and immune response control bleeding and prevent infection. Subsequently, various cells proliferate, differentiate, and migrate, leading to the formation of granulation tissue. This tissue then undergoes remodeling, and the scar contracts, ultimately achieving complete healing83. An ideal wound healing material should possess adhesion, ease of processing, biodegradability, breathability, and antibacterial and anti-inflammatory properties84. During wound healing, mesoporous silica nanoparticles (MSN) and bioactive glass nanoparticles (BG-NP) can construct biological scaffolds that mimic the extracellular matrix, providing a supportive structure for cell attachment and promoting cell adhesion, proliferation, and migration85. These nanoparticles can also serve as additive components, combining with other materials to form SNs. For instance, when combined with hydrogels—highly hydrated, injectable, and similar to the extracellular matrix—they help create a microenvironment conducive to wound healing86,87. Furthermore, they can be used as drug carriers to deliver anti-inflammatory drugs, antibacterial agents, and other medications33,88.
Hemostasis is the initial stage of wound healing (Fig. 12a). When tissue is damaged, it releases vasoactive substances that constrict local blood vessels. Simultaneously, platelets are recruited and activate the coagulation cascade, forming a fibrin clot that protects the exposed wound tissues and prevents further loss of body fluid89. MSN with specific pore sizes, even without loaded drugs, can expose blood proteins to their large interior surfaces, thereby triggering the coagulation cascade90. Additionally, it has been shown that bioactive glass nanoparticles (BG-NP) combined with tannic acid (TA), which possesses vasoconstrictive properties, can facilitate hemostasis91,92. A silica-based nanocomposite (Ca-TA-MSN@Ag) was developed to further enhance hemostasis using TA and coagulation factor IV (Ca2+). TA constricts blood vessels during the hemostasis process, while Ca2+ and MSN activate the coagulation cascade. This activation induces red blood cells and fibrin to form a three-dimensional network that effectively halts bleeding. The embedded silver nanoparticles provide additional antibacterial properties, helping to prevent infection93. Therefore, utilizing SNs in combination with procoagulants represents a viable approach for achieving rapid hemostasis.
a Hemostasis promotion: (I) MSN combined with tannic acid (TA) promotes vasoconstriction. (II) Coagulation factor IV stimulates fibrin production. (III) Silver (Ag) nanoparticles exhibit antibacterial activity. b Inflammation regulation: (I) MSN-delivering cerium oxide (CeO) nanoparticles neutralize ROS produced in tissue cells and secreted by inflammatory cells through the conversion of Ce3+ and Ce4+, inhibiting tissue cell aging and regulating inflammation at the molecular level. (II) Resveratrol-loaded MSN influences macrophage polarization and the secretion of anti-inflammatory factors, regulating inflammation at the cellular level. (III) A novel MSN composite membrane facilitates the drainage of excess inflammatory exudate, regulating inflammation at the tissue level. c Proliferation regulation: Astragalus-loaded MSN promotes endothelial cell proliferation and collagen production. d Tissue Remodeling Improvement: Fe-curcumin chelate-loaded MSN inhibits excessive fibroblast proliferation, preventing scarring
Inflammation is a complex defense response in the body. The various stages of wound healing are initiated by a cascade of reactions involving immune cells and the signaling molecules they release89. In the early stages of wound healing, inflammation is beneficial as it helps remove harmful substances and dead tissue, fights off bacterial invasion, and promotes cell proliferation. However, in the later stages, wound healing can be hindered by factors such as excessive levels of ROS, prolonged inflammation, and inflammatory exudates, leading to a delayed healing process94,95. Although ROS has some antibacterial properties, excessive levels around wounds can cause cell aging and scarring. To tackle this issue, MSN is combined with ROS-scavenging ceria nanoparticles to form nanocomposites that eliminate excess ROS around wounds, thereby protecting cells from oxidative stress and promoting wound healing49,96,97. Furthermore, the phenotypic transition of macrophages provides valuable insights into managing inflammation. During the late stages of wound healing, macrophages respond to the microenvironment by shifting to the M2 phenotype, which suppresses inflammation and promotes wound healing98. Based on this, resveratrol-loaded MSN can induce M2 macrophage polarization, promoting the expression of anti-inflammatory factors such as TGF-β1 and Arg-1, thus achieving anti-inflammatory effects99. Additionally, the large volume of wound exudate resulting from the inflammatory response negatively impacts the healing process95. A specially structured MSN composite membrane offers an effective solution to this problem. This membrane has an outermost hydrophilic layer that creates a continuous capillary pull, while the hydrophobic middle layer exerts a pushing force. Together, these layers facilitate the drainage of excess inflammatory exudates, and the innermost drug carrier layer contains curcumin, providing antibacterial protection to prevent wound infection8. Overall, MSN can regulate inflammation at the molecular, cellular, and tissue levels to promote wound healing (Fig. 12b).
Proliferation is a critical stage in wound healing, encompassing angiogenesis and granulation tissue formation. Vascular endothelial cells and fibroblasts are the primary cells involved during this phase. Neovascularization ensures blood supply and nutrition to the wound as necrotic tissue is cleared and inflammation diminishes. This process stimulates endothelial cell proliferation and migration under the influence of growth factors, promoting angiogenesis89,100. Concurrently, fibroblasts proliferate and migrate, secreting extracellular matrix to facilitate wound healing100. Our study revealed that MSN loaded with Astragalus induced the proliferation of umbilical vein endothelial cells, enhancing neovascularization by regulating growth factors through the JAK2/STAT3 pathway. Notably, an increase in collagen content was observed in vivo, indicating that the material may also somewhat promote fibroblast proliferation and secretion101. However, abnormal fibroblast proliferation and excessive extracellular matrix secretion can lead to hypertrophic scarring102, adversely affecting skin appearance and the functional integrity of the healed tissue103. To mitigate this, MSN loaded with Fe-curcumin chelate can inhibit excessive fibroblast proliferation, reduce scar formation, and effectively promote wound healing104. Thus, SNs can simultaneously promote cell proliferation and minimize scarring, thereby improving skin structure and function recovery (Fig. 12c).
In conclusion, SNs have potential applications in various crucial stages of wound healing, such as hemostasis, inflammatory response, tissue remodeling, cell proliferation, and differentiation. However, most current research on SNs for wound healing focuses on exploring the mechanisms and verifying treatment effects in vitro and animal models, with a significant lack of clinical studies. Therefore, it is essential to enhance clinical research and develop SNs in alignment with clinical needs to facilitate the translation of research findings into clinical practice.
Future research trends and emerging frontiers
In recent years, the use of MBGNP has steadily increased. Keyword burst analysis (Fig. 6b) highlights “Mesoporous Bioactive Glass Nanoparticle” as a frequently cited keyword over the past five years, while co-citation clustering (Fig. 5, cluster #5) supports the strong theoretical foundation of MBGNP. Compared to BG-NP, MBGNP exhibits a higher specific surface area, porosity, and enhanced biological activity in vitro15. The high specific surface area, nanoporous structure, and increased roughness of MBGNP promote cell attachment and biomineralization105. MBGNP serves as a versatile drug carrier106 and doping it with metal ions such as cerium, gallium, and strontium further enhances its properties. Specifically, it improves antibacterial properties27,107, osteogenic differentiation108,109, bioactivity110, and protein adsorption capacity111. Strontium ions, commonly used in MBGNP for bone engineering, facilitate bone formation and reduce resorption14. Sr-MBGNP also supports biomineralization and matrix reconstruction112. Incorporating therapeutic metal ions into MBGNP takes advantage of its mesoporous structure for drug delivery, making it a promising candidate in regenerative medicine57.
To improve therapeutic outcomes and meet various clinical needs, multifunctional SNs (Smart Nanomaterials) can be developed by integrating multiple materials that possess unique advantages. For example, electrophoretic deposition can be used to create tri-functional composite coatings on implant surfaces, which provide antibacterial properties, promote angiogenesis, and enhance bone integration113. Furthermore, 3D printing technology can produce biomimetic scaffolds with layered or “flower bed” structures that promote angiogenesis, support bone regeneration, and facilitate inward infiltration growth73,114. Currently, research has shifted from preparing and characterizing SNs to exploring their multifunctional properties. The utilization of MBGNP and the development of silica-based nanocomposites are emerging as significant research trends for the future.
Challenges
Over the past three years, related research has been conducted extensively. However, cutting-edge research has identified some issues that require attention. Firstly, the specific mechanism by which MBGNP promotes osteogenesis remains unknown. It is speculated that MBGNP degradation may release Ca2+ and SiO44-, accelerating osteoblast differentiation by activating the PI3K/AKT pathway69. Secondly, most current SNs (Smart Nanomaterials) lack the multi-stage facilitation that mimics natural tissue regeneration. While existing studies aim to promote tissue repair through multiple pathways112, they often overlook that tissue regeneration is a spatiotemporally regulated and highly coordinated process. Premature drug release or treatment strategies targeting only a single enhancement stage can prolong tissue regeneration time91. Therefore, designing the structure and function of SNs from a sequential therapy perspective may yield better clinical outcomes. Thirdly, using SNs to promote tissue regeneration becomes more challenging in the presence of systemic diseases, such as diabetes mellitus, which can cause a persistent hyperglycemic inflammatory microenvironment, reduced angiogenesis, granulation tissue formation, and co-infections112. Lastly, as more and more components are introduced into SNs, their functions become increasingly diverse. However, the complex production steps involved seem to hinder industrial-scale preparation and clinical translation. Therefore, there is a need to develop a simple yet efficient multifunctional SNs platform115. Among these, metal ion-regulated composite hydrogels can regenerate critical bone defects in rats without the need for expensive cytokines or time-consuming cell processing116. In addition to the contradiction between multifunctionality and large-scale industrial production, it is also necessary to supplement large animal model validation117, improve long-term biosafety data, and establish a systematic toxicology research system to further promote the clinical translation process of SNs115. In summary, the unclear osteogenic mechanisms of MBGNP, the need for structural and functional design of SNs under sequential therapy strategies, the impact of other diseases on tissue regeneration, and the challenges in clinical translation will likely be the challenges and difficulties faced in the future.
Conclusion
This paper has comprehensively examined research trends, hotspots, and recent advancements in SNs for regenerative medicine, utilizing data-driven visualization and analysis. Over the past five years, there has been significant growth in this area, with notable contributions from American authors and impactful publications in Bioactive Materials, especially from the University of Erlangen-Nuremberg. Key research areas include drug delivery, antimicrobial activity, bone regeneration, and wound healing, with MBGNP currently considered ideal drug carriers. To enhance their applications in bone regeneration, future research should focus on surface functionalization. Furthermore, to optimize therapeutic effects, the development of SNs must achieve precise spatiotemporal regulation across various stages of tissue regeneration, requiring improved control over drug release mechanisms. This study has organized relevant fundamental theoretical literature and highlighted recent progress in research hotspots, providing a valuable reference for researchers and practitioners. Hopefully, this work will inspire further investigations into the design and functionalization of SNs.
Data availability
Data are available and located in the supplementary materials.
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The authors acknowledge the software engineers who provided analysis tools, including CiteSpace, VOSviewer, and Biblioshiny.
Funding
This research was funded by the National Natural Science Foundation of China (32301129, 82150410451), the Science and Technology Planning Projects of Guangzhou City, China (No. 202201020203), and the Undergraduate Teaching Quality and Teaching Reform Engineering Projects of Guangzhou Medical University (No. 2023ZLGC080, 2022-124-1).
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Chengxi Yang: Writing-review & editing, Writing-original draft, Visualization, Software, Methodology, Formal analysis, Data Curation. Zhenhuan Xie: Date re-analysis and modified this work. Sihua Liang and Zhan Liu: Data collection, Writing-original draft, Visualization. Luís Cardoso and Dan Hou: Review and supervision. Janak Lal Pathak and Qing Zhang: Writing—review & editing, Supervision, Resources, Project administration, Funding acquisition, Conceptualization.
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Yang, C., Xie, Z., Liang, S. et al. Data-driven visualization of silica-based nanobiomaterial dynamics for tissue regeneration. Microsyst Nanoeng 12, 31 (2026). https://doi.org/10.1038/s41378-025-01120-0
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DOI: https://doi.org/10.1038/s41378-025-01120-0
