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. 2025 Dec 24;76(1):109348. doi: 10.1016/j.identj.2025.109348

Nanoplatform-Enhanced Photodynamic Therapy in Head and Neck Squamous Cell Carcinoma: Advances and Future Directions

Weiqian Zhang a,†, Menglai Gan b,†, Yu He a, Wenbo Ma a, Sai Liu b,⁎, Dongjuan Liu a,⁎
PMCID: PMC12800409  PMID: 41447821

Graphical abstract

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Key words: Photodynamic therapy, Head and neck squamous cell carcinoma, Nanotechnology, Tumour microenvironment, Cancer therapy

Abstract

Introduction and Aims

Photodynamic therapy (PDT) has become a promising treatment for head and neck squamous cell carcinoma over the past 25 years, with nanotechnology accelerating its development. This study aimed to systematically map research trends, thematic evolutions, and technological advances in nano-enhanced PDT for head and neck squamous cell carcinoma.

Methods

A bibliometric and trend analysis was performed on 736 English-language publications from January 2000 to June 2025, sourced from the Web of Science Core Collection. CiteSpace/VOSviewer, BICOMB, gCLUTO, and related visualization tools were applied to analyse global research contributions, collaboration networks, keyword clusters, and technological breakthroughs.

Results

Annual publications increased from fewer than 30 (2000-2011) to over 50 (2022-2025), with China, the United States, and the United Kingdom as leading contributors. International collaborations have become more multipolar over time. Three major thematic clusters emerged: (1) fundamental PDT mechanisms, (2) nano-enhanced delivery systems and modulation of the tumour microenvironment, and (3) multimodal combination therapies. Recent growth in publications has been driven by nanoplatforms employing passive and active tumour targeting, along with oxygen-generating strategies.

Conclusion

Although nano-enhanced PDT has achieved substantial preclinical progress, its clinical translation remains limited by manufacturing variability, regulatory uncertainty, and cost-effectiveness concerns. Progress will require well-designed multicentre trials, standardized nanomaterial characterization, and early incorporation of health-economic evaluation. By charting the integration of nanotechnology into PDT and identifying opportunities for synergistic and theranostic approaches, this research provides a structured reference to support future clinical translation.

Clinical relevance

Nano-enhanced PDT holds strong potential to improve treatment precision, reduce side effects, and address resistance in HNSCC, offering new strategies for both early-stage lesions and advanced tumours. By clarifying global research patterns and identifying key innovation areas, this study supports more effective clinical translation and evidence-based adoption of nano-enhanced PDT into head and neck cancer care pathways.

Introduction

Head and neck squamous cell carcinoma (HNSCC) remains a formidable global health challenge, with 890,000 new cases and 450,000 deaths reported annually.1, 2, 3 Despite advances in conventional treatments, the 5-year survival rate remains below 50% in advanced cases.4,5 Traditional therapeutic modalities are frequently associated with substantial functional impairment, aesthetic concerns, and considerable toxicity, underscoring the urgent need for more effective and less invasive treatment strategies.6

Photodynamic therapy (PDT) has emerged as a promising alternative or adjunctive approach for HNSCC due to its minimally invasive nature and ability to selectively target tumour cells while sparing healthy tissue.7, 8, 9 PDT utilizes light-activated photosensitizers (PSs) to generate cytotoxic reactive oxygen species, inducing tumour cell death.10, 11, 12 However, clinical application of PDT in HNSCC has been hampered by several intrinsic limitations, including inadequate tissue penetration of activating light, tumour hypoxia, and insufficient PS specificity, which collectively restrict its therapeutic efficacy.13,14

In recent years, the integration of nanotechnology has revolutionized the landscape of PDT for HNSCC.15, 16, 17 Nanoplatforms offer innovative solutions to longstanding challenges by enhancing PS delivery, improving tissue penetration, and modulating the tumour microenvironment.18,19 These technological advancements have not only expanded the therapeutic potential of PDT but also stimulated interdisciplinary research and the development of combination therapies.

Despite the growing interest and rapid progress in this field, a comprehensive understanding of global research trends, collaborative networks, and emerging hotspots, particularly in relation to nano-enabled PDT, remains lacking. To address this gap, the present study conducts a systematic bibliometric and trend analysis of publications from 2000 to 2025, aiming to map the evolution of research themes and technological breakthroughs in PDT for HNSCC, evaluate the impact of nanotechnology integration, and provide evidence-based insights for future research and clinical translation. Understanding these trends is crucial for guiding future investigations, optimizing resource allocation, and ultimately improving patient outcomes in HNSCC.

Material and methods

We systematically retrieved publications from the Web of Science Core Collection (WoSCC) database to comprehensively capture the evolution of nano-enabled PDT for HNSCC over the past 25 years. The Web of Science Core Collection was selected due to its standardized bibliographic records and comprehensive citation information, making it one of the most reliable sources for bibliometric analysis. The search was conducted on 30 June 2025, and covered the period from 1 January 2000 to 30 June 2025. The search terms are as follows: TS = (((‘head and neck’ OR ‘oral’ OR ‘oropharyngeal’ OR ‘laryngeal’ OR ‘nasopharyngeal’) AND (‘cancer*’ OR ‘carcinoma*’ OR ‘squamous cell carcinoma*’)) AND (‘photodynamic therap*’ OR ‘photodynamic treatment*’ OR ‘PDT’)). Inclusion criteria were the following1: Publications indexed in the Web of Science Core Collection (WoSCC)2; written in English3; published between 1 January 2000 and 30 June 20254; focused on PDT, nanotechnology/nanomaterials, and HNSCC. Exclusion criteria were the following1: Duplicate publications2; records lacking complete bibliometric information3; publications that did not simultaneously address PDT, nanotechnology, and HNSCC, including those that only mentioned related keywords superficially. The data retrieval and collection procedure are shown in Figure 1. To ensure consistency in data analysis, synonymous terms (eg, ‘photodynamic therapy’ and ‘PDT’) were manually unified. Literature information extracted from WoSCC was analysed and visualized through CiteSpace (version 6.4.1), VOSviewer (version 1.6.20), BICOMB (version 2.0), gCLUTO (version 1.2), and GraphPad Prism (version 9.5.1).

Fig. 1.

Fig 1

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Flow diagram of study selection and data analysis strategies.

Results

From January 2000 to June 2025, a total of 736 publications focusing on PDT for HNSCC were retrieved, reflecting the rapid evolution of this research field over the past 25 years (Figure 2). The annual publication output demonstrated a generally upward trajectory, which can be categorized into three distinct phases. The slow growth phase (2000-2011) was followed by an acceleration phase (2012-2021), PDT began to attract more attention as a promising therapeutic modality for HNSCC. Since 2022, the field has entered a period of rapid expansion. This sharp increase may be attributed to the growing recognition of PDT’s clinical potential and the integration of nanotechnology, which has revitalized interest and innovation in the field.

Fig. 2.

Fig 2

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(A) Pie chart showing the article types. (B) Global publication output. Note: The annual publication statistics for 2025 only include publications released up to 30 June 2025.

The 736 publications originated from countries/regions worldwide, demonstrating the global interest in PDT for HNSCC. This distribution highlights the emergence of both established and rising research powers in this domain. China led with 270 publications, followed by the United States (144 publications) and the United Kingdom (48 publications), collectively accounting for over 60% of the total output. Analysis of international collaboration networks revealed complex and dynamic connections among countries and regions (Figure 3). The collaboration network has expanded in scale, with decreasing centralization and increasing multipolarity, reflecting the rise of emerging countries and more balanced global participation in the field.

Fig. 3.

Fig 3

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Publication activity based on number of publications and the network of international collaborations.

The top 3 institutions by publication volume are the University of London (32 articles), the Netherlands Cancer Institute,27 and National Cancer Centre Singapore.23 The author collaboration network further illustrates the academic influence and cooperative relationships among leading scholars (Figure 4A). Colin Hopper is the most prolific author, with research spanning multiple countries and encompassing clinical applications, diagnostic technologies, and combination therapies in PDT for HNSCC (Figure 4B).

Fig. 4.

Fig 4

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(A) Collaboration network of institutions. (B) Collaboration network of authors. (C) Clusters of high-publication authors.

The most-cited articles primarily focus on the mechanisms of PDT, clinical application outcomes, and the development of novel PSs and nanoplatforms.20 Foundational studies on PDT mechanisms continue to be referenced, while more recent surges in citations are associated with advances in nanotechnology integration and combination therapies (Table). In terms of subject categories, the majority of publications are indexed under oncology, dentistry, surgery, materials science, and biomedical engineering, illustrating the broad relevance of PDT for HNSCC across both clinical and basic research domains. The convergence of these fields has accelerated the translation of laboratory discoveries into clinical practice, as evidenced by the increasing number of translational research articles in recent years.

Table.

Top 10 cited original articles.

Study Research focus Key findings/contribution Citations References
Karakullukcu et al Clinical efficacy
  • •

    PDT for early-stage oral/oropharyngeal neoplasms

  • •

    Stratified outcomes by stage, site, and recurrence

  • •

    Durable local control with low morbidity

 16 21
Li et al Nanotechnology
  • •

    Demonstrated high singlet oxygen yield using S-doped carbon dots as nano-photosensitizers (PSs)

  • •

    • Showed promising in vitro safety profile

 14 22
Rigual et al Clinical efficacy
  • •

    Systematic PDT study for head and neck dysplasia/early cancers

  • •

    High stage-specific remission in premalignant lesions

  • •

    Safe, organ-preserving, minimal toxicity

 14 23
Wang et al Nanotechnology
  • •

    Developed novel nanoparticles (NPs) delivery system

  • •

    Achieved site-specific drug release

  • •

    Enhanced therapeutic efficacy through synergistic PDT, photothermal therapy (PTT), and chemotherapy

 14 24
Wang et al Mechanistic study
  • •

    Verified PDT effectiveness at cellular level

  • •

    Demonstrated dose- and time-dependent inhibition

  • •

    Induced apoptosis in cancer cell lines

 13 25
D’Cruz et al Clinical efficacy
  • •

    Multicentre mTHPC-PDT in advanced head and neck cancer

  • •

    Assessed tumour response and quality of life

  • •

    Greater efficacy in smaller, fully irradiated lesions

 12 26
Jerjes et al Clinical efficacy
  • •

    mTHPC-PDT in T1/T2 N0 oral squamous cell carcinoma

  • •

    Long-term tumour control with minimal morbidity

  • •

    PDT as a less invasive, organ-preserving alternative

 12 27
Tao et al Nanotechnology
  • •

    Designed size-shrinkable NPs

  • •

    Enhanced delivery of hypoxia regulator and photodynamic agent

  • •

    Improved PDT efficacy against oral squamous cell carcinoma (OSCC)

 12 28
Wang et al Combination therapy
  • •

    Achieved 90.9% response rate

  • •

    No local recurrence during follow-up

  • •

    Proved safety and efficacy of aminolevulinic 1 acid (ALA)-phoyodynamic therapy (PDT)

 12 29
Wei et al Nanotechnology
  • •

    Developed novel liposomal nanoplatform

  • •

    Combined chemotherapy and catalytic therapy

  • •

    Enabled multimodal imaging-guided treatment

 12 30
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Early years of research were dominated by fundamental studies on PDT mechanisms. As the field matured, Citation Bursts analyses of keywords indicate a clear thematic transition. Research began to diversify, with emerging clusters centred around ‘tumour microenvironment’ and ‘nanoparticles’.31,32 The appearance of these terms as burst keywords underscores the growing emphasis on overcoming traditional PDT limitations through the adoption of nanotechnology and advanced drug delivery systems.33,34 Notably, there has been a paradigm shift towards the integration of PDT with novel nanoplatforms and synergistic treatment modalities (Figure 5A,B. Cluster analysis further demonstrates that research hotspots have gradually shifted from mechanistic and preclinical studies to translational and application-oriented investigations35 (Figure 5C,D).

Fig. 5.

Fig 5

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(A) Keyword co-occurrence network. (B) Top 15 keywords with the strongest citation bursts. Dendrogram (C) and mountain visualization (D) of keywords.

Overall, the evolution of research themes in PDT for HNSCC demonstrates a vibrant and forward-looking scientific landscape. The transition from foundational mechanism studies to advanced, nano-enhanced applications not only highlight the adaptability of the field but also underscores the central role of nanotechnology and interdisciplinary collaboration in driving future breakthroughs. This thematic progression provides a roadmap for identifying emerging hotspots and guiding future research directions in the quest for more effective and personalized therapeutic strategies.36

Discussion

Overall trends from bibliometric analysis

Our bibliometric mapping of 736 publications from 2000 to 2025 highlights a marked and accelerating growth of PDT research in HNSCC. Annual output remained modest until 2011, followed by steady acceleration and a rapid surge since 2022. China, the United States, and the United Kingdom lead in productivity, yet a multipolar collaboration pattern is emerging, with contributions from Asia, South America, and Eastern Europe increasingly visible.

Keyword co-occurrence and burst detection analyses indicate a significant thematic shift – from early emphasis on photophysical mechanisms and clinical efficacy of PDT towards ‘nanoparticles’, ‘tumour microenvironment’, and ‘combination therapy’.37, 38, 39 Cluster analysis further confirms that traditional mechanistic studies are being complemented or replaced by work on nano-enhanced delivery, hypoxia modulation, and multimodal regimens.40,41 These changes mirror enduring clinical challenges, including limited light penetration, tumour hypoxia, and suboptimal PS specificity, which nanotechnology is particularly well suited to address.42, 43, 44

Role of nanotechnology in emerging hotspots

Our study identified four major emerging hotspots in nano-enhanced PDT for HNSCC: enhancing drug delivery efficiency, modulating the tumour microenvironment, improving PDT tissue penetration, and developing multimodal combination therapies (Figure 6). These hotspots not only highlight current advances but also point to promising directions for future research and clinical translation.

Fig. 6.

Fig 6

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Three emerging nano-enhanced PDT strategies in HNSCC, as identified from bibliometric hotspot analysis and representative studies. (A) Enhancing drug delivery efficiency: Nanocarriers protect PSs from degradation, enable controlled release, and promote immune evasion. (B) Modulating tumour microenvironment: Oxygen carriers (eg, Hb-based, RBC mimics) and oxygen-generating nanoplatforms (eg, Mn-doped carbon dots, catalytic nanozymes) relieve tumour hypoxia and enhance ROS production. (C) Improving PDT tissue penetration: UCNPs, two-photon excitation nanomaterials, and nano-microneedles enable PS activation at greater depths with high spatial precision. (D) Driving multimodal combination therapies: Codelivery of PSs with chemotherapeutics, immunomodulators, or gene silencers amplifies therapeutic effects through synergistic mechanisms. DC, dendritic cell; ICI, immune checkpoint inhibitors; NIR, near-infrared; UCNP, upconversion nanoparticles.

Enhancing drug delivery efficiency. The prominence of ‘nanoparticles’ and ‘drug delivery’ in both clustering and burst term analyses reflects the field’s shift towards improving PS pharmacokinetics and tumour targeting.45,46 Nanocarriers effectively shield drugs from enzymatic degradation and metabolic breakdown within the body, thereby significantly enhancing their stability.32 The encapsulation and surface modification of nanomaterials are also continuously optimized to enhance their stability and biocompatibility in vivo.47, 48, 49 For instance, Chen et al50 developed bone-targeted erythrocyte-cancer hybrid membrane-camouflaged nanoparticles that achieve efficient bone targeting through modification with an octapeptide (Asp8) for high bone affinity and enhanced immune evasion.

Modulating tumour microenvironment. The recent burst of ‘tumour microenvironment’ reflects intensified focus on overcoming hypoxia in PDT. Oxygen carriers such as haemoglobin-based nanoparticles, biomimetic nanoscale red blood cells, and MOFs can deliver exogenous oxygen,35,51 while catalytic nanomaterials generate oxygen in situ using the tumour’s elevated H₂O₂.52, 53, 54 Zhu et al55 reported fluorinated chitosan–Ce6 nanoparticles with catalase, increasing intracellular oxygen and reducing hypoxia, while Zhang et al56 utilized Mn-doped carbon dots as nanozymes to catalyse oxygen generation under acidic, H₂O₂-rich conditions, significantly improving PDT efficacy against oral squamous cell carcinoma cells.

Improving PDT tissue penetration. Nano-microneedles, an innovative local delivery technology, offer efficient and controllable drug release. Although less frequent in literature volume, ‘upconverting nanoparticles (UCNPs)’ and ‘two-photon’ systems show clear upward trajectories. UCNPs are a special type of optical material that can convert low-energy near infrared (NIR) light into high-energy visible light. NIR light can penetrate biological tissues more deeply, reducing damage to healthy tissues.57, 58, 59 Dash et al60 prepared methotrexate-loaded dumbbell-shaped titanium dioxide/gold nanorods coated with mesoporous silica and decorated with UCNPs. Under NIR laser irradiation, these nanocomposites effectively killed oral squamous cell carcinoma cells (HSC-3) without inducing toxicity and demonstrated excellent antitumour effects in vivo. Similarly, Nasrin et al61 synthesized conjugated carbon dots functioning as two-photon PSs, generating ROS efficiently under 780 nm excitation.

Multimodal combination therapy strategies. The emergence of ‘combination therapy’ as a major keyword reflects the growing shift from monotherapy PDT to synergistic strategies enabled by nanotechnology. PDT-chemotherapy is the most established approach, exemplified by nanoparticles coloaded with PSs and cisplatin that achieve coordinated cytotoxic effects.24 Increasing attention has also been given to PDT-immunotherapy, where PDT-induced immunogenic cell death generates tumour antigens that synergize with immune checkpoint inhibitors or vaccine adjuvants, producing robust antitumour immunity.62 Gene therapy combined with PDT, such as VEGF-A siRNA delivery via nanoparticles, has shown marked inhibition of tumour growth and angiogenesis, addressing resistance mechanisms.63,64 Collectively, multimodal strategies represent a key direction for future development of nano-enhanced PDT in HNSCC.

Challenges for clinical translation

Despite the promising preclinical results of PDT enhanced by nanotechnology, its translation into clinical practice remains limited. Currently, PDT is implemented in select clinical settings for HNSCC, primarily as an adjunct treatment for early-stage or superficial lesions.65, 66, 67 Barriers include: (1) Manufacturing and standardization: The diversity of nanomaterial compositions and drug-loading processes impedes reproducibility.53 (2) Safety and regulatory hurdles: The long-term biodistribution, degradation products, and potential immunogenicity of nanocarriers require thorough investigation.68 (3) Economic and accessibility constraints: Cost-effectiveness analyses are rare, and scaling production for widespread use remains a challenge. Addressing these issues demands coordinated multicentre trials, harmonized characterization protocols, and integration of health-economic metrics into early development.

Future research directions

Advancing targeted nano-delivery systems. Future advances in nano-enhanced PDT for HNSCC are expected to centre on innovative strategies, particularly more precise targeting approaches.69,70 Advances in nano-delivery systems will continue to enhance targeting precision and therapeutic efficacy.59 In parallel, the design of ‘smart’ nanoplatforms capable of responding to tumour-specific microenvironmental cues such as pH, ROS, and enzymes has emerged as a promising strategy to achieve controllable drug release, further improving treatment selectivity and safety.71

Personalized and intelligent PDT optimization. The personalization and intelligent optimization of PDT protocols are expected to shape the next generation of therapies. Treatment customization based on tumour molecular characteristics – including PS selection, nanoplatform design, and dosing strategies – may substantially improve outcomes.72 Furthermore, the integration of artificial intelligence and machine learning will likely play a pivotal role by analysing molecular profiles, predicting responses, and guiding the adjustment of PS type, light wavelength, and dose scheduling, thereby enabling more precise and individualized PDT interventions.73,74

Integrating emerging therapeutic modalities. Emerging treatment modalities are being integrated with PDT to create novel therapeutic paradigms. Sonodynamic therapy utilizes ultrasound activation of sonosensitizers, offering deep tissue penetration and precise spatial control. Chemodynamic therapy exploits Fenton-like reactions to generate reactive oxygen species, creating synergistic effects with PDT.75 Beyond these, ferroptosis-inducing agents combined with PDT establish a powerful oxidative stress paradigm capable of overcoming conventional resistance mechanisms.76, 77, 78 In addition, gas therapy – using nitric oxide, hydrogen sulphide, or carbon monoxide delivered via nanocarriers – represents another promising approach to augment PDT efficacy.79

Innovations and limitations of this study

While several bibliometric analyses have addressed the general progress of PDT in oncology, there is still a lack of comprehensive bibliometric studies specifically focused on the application of PDT in HNSCC.80, 81, 82, 83, 84 Our study identifies the shift from foundational mechanistic studies to nano-enhanced therapies,85, 86, 87 and based on this 25-year bibliometric analysis, outlines major trends, mechanisms, and future directions for nano-enhanced PDT in HNSCC.88, 89, 90, 91

However, the analysis has several limitations. First, it is limited to English-language publications indexed in the Web of Science Core Collection, which may introduce both language bias and publication availability bias. Second, the dataset for 2025 includes publications only up to June 30, which may underestimate the full-year output and affect the growth rate and keyword trends for the most recent period. Despite these limitations, our study provides valuable insights into the evolving landscape, challenges, and future opportunities in nano-enhanced PDT for HNSCC.

Conclusions

Over the past 25 years, research on PDT in HNSCC has undergone a distinct transition from early mechanistic and clinical investigations to a strong focus on nano-enhanced strategies. Bibliometric analysis reveals emerging hotspots – enhancing drug delivery efficiency, modulating the tumour microenvironment, improving PDT tissue penetration, and driving multimodal combination therapies. These advances directly target long-standing limitations of PDT, such as insufficient light penetration, tumour hypoxia, and limited PS specificity.

Despite significant progress in preclinical research, the translation of nano-enhanced PDT into routine clinical practice remains constrained by manufacturing variability, regulatory uncertainty, and cost-effectiveness considerations. Addressing these challenges will require coordinated multicentre trials, standardized nanomaterial characterization, and integration of economic assessments early in development.

By mapping global research trends and pinpointing key technological frontiers, this study provides a timely and structured reference for researchers and clinicians seeking to optimize PDT for HNSCC. The insights gained can inform targeted research investments, foster cross-disciplinary collaborations, and ultimately accelerate the clinical integration of nano-enhanced PDT.

Funding

The study was supported by the National Natural Science Foundation of China (No. 82270989 and 81902772), Natural Science Foundation of Liaoning Province (No. 2022-MS-206 and 2022-MS-200), and Foundation of Liaoning Educational Committee (No. JYTMS20230115).

Author contributions

Dongjuan Liu and Sai Liu have made substantial contributions to the conception, and were a major contributor in designing the work; Weiqian Zhang has drafted the work or substantively revised it; Menglai Gan has made contributions to the analysis of data; Yu He and Wenbo Ma have made contributions to the acquisition and interpretation of data. All authors read and approved the final manuscript.

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.

Contributor Information

Sai Liu, Email: liusai@cmu.edu.cn.

Dongjuan Liu, Email: dongjuanliu@cmu.edu.cn.

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