4.1 General information

This study provides the first comprehensive bibliometric analysis of NDDS in LC, highlighting significant research growth since 2009. The increase in publications underscores NDDS’s rising importance in LC treatment, reflecting global institutions' strong commitment and establishing NDDS as a key focus in cancer research.

The analysis reveals a disparity between publication volume and research impact. While China leads in publications, countries like the United States and European nations achieve higher citation rates despite fewer papers. The U.S., in particular, shows the strongest citation burst (strength = 22) (Supplementary Fig. 4), suggesting China’s research output has not yet matched its global influence. This could be attributed to the differences in research practices and international collaboration. While China has made substantial investments in research funding, the U.S. and European countries benefit from stronger collaborative networks and a focus on publishing in high-impact journals, which amplify their citation rates and global influence.Strengthening partnerships could help close it.

Additionally, 60% of the top 10 institutions by publication and citation frequency are from China. Citation burst analysis highlights institutions like Saveetha Institute of Medical & Technical Science (strength = 9.33), Soochow University (strength = 8.14), and the Chinese Academy of Sciences (strength = 7.73) (Supplementary Fig. 5) for their rapid international recognition. These Chinese institutions excel due to significant government funding and strategic focus on emerging fields like nanomedicine. However, the citation performance of institutions such as Saveetha suggests that sustained growth in influence will require deeper international collaborations and higher-impact research outputs to match the influence of their Western counterparts.

In terms of journal impact, the International Journal of Nanomedicine leads in publication volume, while the Journal of Controlled Release excels in co-citation metrics. This difference reflects the distinct focus of these journals: while the International Journal of Nanomedicine caters to a broader audience, the Journal of Controlled Release targets foundational research with higher citation potential. This shows the importance of publishing in journals with strong citation records, like the Journal of Controlled Release, for greater academic influence.

Regarding author influence, Kamal Dua leads in publication output, while researchers like Maeda, H, Zhang, Y, and Wang, Y, have made foundational contributions. Maeda’s work on SMA copolymer-based micellar drugs [23] highlighted the EPR effect, improving drug accumulation in metastatic LC. Zhang’s graphene oxide nanoparticle advancements [24] and Wang’s research on targeting cancer metabolism and telomere dynamics [25, 26] have introduced promising strategies for LC therapies. These researchers’ work has solidified their leadership in advancing NDDS for LC.

4.2 Hotspots and frontiers

Highly co-cited references have played a crucial role in shaping the academic understanding of NDDS in LC (Supplementary Table 4). As shown in Fig. 5B, several key themes emerged in 2024, marking current research hotspots [18, 22, 27, 28]. These highly cited studies highlight cutting-edge trends in NDDS for LC, focusing on personalized treatments, overcoming multidrug resistance, and the optimization and hybridization of nanomaterials. They underscore nanotechnology’s role in enhancing the effectiveness of chemotherapy, targeted therapy, and immunotherapy by specifically targeting cancer cells, thus improving both drug delivery efficiency and patient safety. These studies showcase significant advancements in NDDS for LC and highlight their strong potential for future clinical applications.

Keywords analyses offer critical insights into the field’s core focus and emerging trends. Figure 5C outlines five primary areas of NDDS research in LC treatment: (1) active targeting for precise delivery to tumor cells; (2) optimizing drug delivery systems to enhance targeting, cellular uptake, and biodistribution; (3) addressing drug resistance through combination therapies to improve treatment efficacy; (4) using nanocarriers like liposomes and micelles to improve biocompatibility and precision in drug delivery; and (5) inhalation-based pulmonary drug delivery, which reduces side effects and increases drug concentration at the tumor site. Looking ahead, emerging trends include epithelial-mesenchymal transition, mucus penetration, lipid nanoparticles, hydrogels, and immune checkpoint inhibitors.

4.3 Advancements in NDDS for LC: key strategies and emerging approaches4.3.1 Active targeting: improving precision in tumor-specific drug delivery

Active targeting in nanomedicine, especially for LC, holds great potential. By modifying nanocarriers with ligands like RGD peptides, folic acid, or hyaluronic acid, these systems selectively bind to overexpressed receptors on tumor cells (e.g., integrin αvβ3, folate receptor, CD44), enhancing drug accumulation at tumor sites and reducing systemic toxicity. Unlike passive targeting, which relies on the EPR effect, active targeting improves precision through receptor-ligand interactions, leading to more effective drug delivery.

For LC, RGD-modified PLGA nanocarriers target integrin αvβ3 receptors on NSCLC cells, improving drug specificity and therapeutic efficacy [29, 30]. Similarly, folic acid-modified quantum dots and liposomes target folate receptors, increasing drug delivery and cellular uptake [31]. Hyaluronic acid-modified systems target CD44 receptors, further enhancing drug delivery to cancer stem cells [32].

Future research could explore combining multiple targeting strategies, such as dual targeting with RGD peptides and folic acid, to improve drug accumulation and overcome tumor microenvironment barriers [32, 33]. When integrated with treatments like chemotherapy or immunotherapy, these advanced nanotechnologies could greatly enhance LC treatment outcomes.

4.3.2 Optimizing NDDS: enhancing targeting, cellular uptake, and biodistribution

Optimizing NDDS requires enhancing targeting, cellular uptake, and biodistribution to maximize therapeutic benefits. Surface modification with targeting ligands like folic acid, transferrin, or EGFR improves tumor-specific recognition, enabling more precise drug delivery and reducing side effects by minimizing toxicity to healthy tissues [34, 35].

Size and surface charge are also key factors. Nanoparticles in the 10–200 nm range enter tumor cells more easily via diffusion and endocytosis, while negatively charged particles often show higher uptake efficiency [34, 36].

Optimizing biodistribution involves adjusting nanoparticle design to influence metabolism and clearance pathways. Changes in size, shape, and surface properties can extend circulation time, reduce rapid kidney clearance, and increase drug accumulation at the tumor site [37]. These adjustments enhance drug efficacy while lowering systemic toxicity, highlighting NDDS's clinical potential [36].

Overall, refining nanoparticle targeting and bioavailability offers promising strategies for improving LC treatment. Future research should continue to focus on these areas for safer and more effective therapies.

4.3.3 Combating drug resistance: utilizing combination therapies for enhanced efficacy

NDDS play a vital role in supporting combination therapies to overcome drug resistance in LC. By co-delivering anticancer agents, NDDS integrate chemotherapy, immunotherapy, and targeted therapies to address resistance caused by tumor heterogeneity, the tumor microenvironment, and efflux proteins like P-glycoprotein [38, 39]. Nanocarriers penetrate the tumor microenvironment more effectively and reduce drug expulsion by efflux proteins, resulting in higher drug concentrations in resistant tumor cells [40].

Additionally, nanotechnology enables controlled drug release and precise targeting, reducing side effects. Research shows nanocarriers can co-deliver multiple drugs while inhibiting resistance-related proteins like ABC efflux pumps, increasing tumor sensitivity to chemotherapy [38]. Future studies should explore how NDDS-based combination therapies can further improve treatment efficacy and combat multidrug resistance [39].

4.3.4 Nanocarriers in NDDS: improving biocompatibility and targeted delivery

Nanocarriers are key to NDDS, enhancing drug biocompatibility and precision targeting. By optimizing surface modifications, shape, and size, nanocarriers can evade immune detection, extend circulation time, and improve stability and targeting efficiency. Nanostructured lipid carriers (NLCs) and polymer-based nanoparticles are especially effective in cancer therapies, increasing drug solubility and reducing side effects [41, 42]. Active targeting, such as functionalizing nanoparticles with ligands like RGD peptides or folate receptors, ensures precise drug delivery to tumor sites. RGD peptides bind to integrin receptors on tumor cells, improving cellular uptake and drug accumulation [43, 44]. These strategies enhance treatment efficacy and reduce systemic toxicity, paving the way for future precision therapies.

4.3.5 Pulmonary drug delivery via inhalation: minimizing side effects and maximizing tumor targeting

Inhalable NDDS provide key benefits for LC treatment by delivering drugs directly to lung tumors, avoiding systemic side effects like liver and kidney toxicity. Nanocarriers improve drug retention in the lungs, enhance mucus barrier penetration, and increase local drug concentration at tumor sites [45, 46]. Optimizing nanoparticle size and surface charge further boosts drug accumulation in lung tumors [47].

Challenges remain, such as overcoming the lung's mucus barrier and immune clearance, as well as patient variability in lung function, which affect drug distribution and efficacy [46, 47]. Future research should focus on developing more biocompatible and responsive nanocarriers with targeting ligands for improved precision [45, 47]. Inhalable NDDS hold great potential for advancing LC therapy.

4.4 Future trends in NDDS for LC4.4.1 Epithelial mesenchymal transition in tumor progression

EMT is a critical process that drives tumor invasion and metastasis. During EMT, epithelial cells lose their polarity and cell-to-cell adhesion, gaining mesenchymal traits like increased motility and invasiveness. This shift not only facilitates tumor spread but also contributes to chemotherapy and radiotherapy resistance by enhancing cancer stem cell characteristics [48, 49].

Targeting EMT through NDDS presents a promising approach to combat drug resistance and prevent metastasis. Nanomaterials can inhibit tumor cell migration and reduce chemotherapy resistance by disrupting EMT-related pathways such as TGF-β, Akt, and Erk1/2 [50, 51]. Future research should aim to develop nanocarriers specifically designed to target EMT, offering the potential to improve treatment outcomes while lowering the risk of metastasis [52].

4.4.2 Mucus penetration for enhanced drug delivery

The mucus layer in the lungs acts as a primary defense mechanism, but it also complicates drug delivery due to its high water content and viscoelastic properties, limiting drug absorption and retention [53].

Recent innovations in nanocarriers, such as PEGylated nanocarriers and liquid crystal nanoparticles, allow drugs to better penetrate the mucus layer and interact with lung epithelial cells, improving retention and increasing local drug concentrations [37, 54]. Some nanocarriers also use adhesion mechanisms or enzymatic actions to break down the mucus structure, further enhancing drug delivery efficiency [53].

Future research should focus on developing advanced nanocarrier systems that combine mucus penetration with targeted delivery, addressing therapeutic challenges in LC. This approach could improve drug bioavailability while reducing systemic side effects [37].

4.4.3 Lipid nanoparticles in targeted therapy

Lipid nanoparticles (LNPs) show great potential for targeted LC therapy. By controlling drug release, LNPs can effectively deliver chemotherapy agents like doxorubicin and paclitaxel to tumors while reducing systemic toxicity [55]. Their biocompatibility and adjustable release properties make them ideal for increasing drug accumulation in tumors and minimizing effects on healthy tissues [56].

LNPs can be further optimized by surface modification with ligands like antibodies or receptor-targeting molecules, allowing selective binding to LC cell receptors and improving treatment efficacy [57]. Beyond chemotherapy, LNPs hold promise for immunotherapy, mRNA vaccines, and CRISPR-based gene editing [58].

Advancements in LNP design and manufacturing will likely expand their role in LC therapy, offering more personalized and effective treatments.

4.4.4 Hydrogels for controlled drug release for LC therapy

Hydrogels, with their three-dimensional crosslinked structures and high water content, are effective for controlled drug release. By using physical or chemical crosslinking, hydrogels regulate drug release rates, especially for large-molecule therapeutics. Their mesh-like networks allow for prolonged and sustained drug delivery, making them ideal for localized, long-term LC treatment [59, 60].

Hydrogels are biocompatible and can respond to stimuli like pH, temperature, light, or enzymes, enabling controlled drug release in response to the tumor microenvironment [61]. This responsiveness enhances delivery precision, improving therapeutic effectiveness while reducing systemic side effects (62). As materials science advances, future hydrogels may integrate nanoparticles for enhanced targeting, offering great potential to improve LC treatment outcomes [62, 63].

4.4.5 Combining NDDS with ICIs in NSCLC therapy

The integration of NDDS with ICIs holds great promise for advancing cancer treatments, particularly in NSCLC. ICIs, such as PD-1 and PD-L1 inhibitors, have improved outcomes by blocking tumor cells from evading immune attacks, but their effectiveness is limited by the immunosuppressive tumor microenvironment, and only a subset of patients responds [64, 65].

Combining ICIs with NDDS can enhance efficacy by precisely delivering drugs to tumors and reducing systemic toxicity. Nanoparticles protect ICIs from rapid degradation, prolonging their action and improving immune responses. For example, dual-functional nanotherapies targeting both PD-L1 and CD47 pathways have shown enhanced activation of both innate and adaptive immune systems, suppressing tumor growth [66, 67].

This combination addresses traditional ICI limitations, reduces resistance, and expands the potential of immunotherapy through nanodelivery systems. As nanotechnology advances, NDDS-ICI combinations are expected to play a key role in LC immunotherapy [67, 68].

4.5 Future challenges and emerging technological opportunities in NDDS and LC4.5.1 Challenges in translating NDDS to clinical applications for LC

Several critical challenges must be addressed to successfully translate NDDS into clinical applications for LC. One key issue is the complexity of nanodrugs, which can lead to unpredictable behavior in the body, particularly in varied tumor microenvironments. Differences in drug distribution, metabolism, and clearance among patients complicate the development of a uniform treatment approach [69].

NDDS also faces regulatory and safety challenges, particularly regarding long-term toxicity and immune responses. Extended retention of nanoparticles in the body may cause unexpected side effects [66, 70].

Additionally, large-scale production poses difficulties. Maintaining key properties like nanoparticle size and surface charge during mass production is challenging, and batch variations can lead to inconsistent efficacy [66].

Future advancements should focus on improving precision in manufacturing processes and implementing standardized quality control to ensure nanodrugs are safe and effective for clinical LC treatments [70, 71].

4.5.2 Emerging technological opportunities for advancing NDDS in LC treatment

The rapid development of smart nanocarriers is creating new opportunities for LC treatment. Responsive designs, such as pH-, temperature-, or redox-sensitive nanoparticles, allow precise drug release within the tumor microenvironment. Since LC tissues often exhibit acidity, many pH-responsive nanocarriers are engineered to release drugs specifically at the tumor site, improving targeted delivery and reducing harm to healthy tissues [35, 72]. These innovations boost drug bioavailability and help overcome tumor drug resistance, leading to better outcomes.

Combining nanomedicine with immunotherapy also holds great promise for LC. When used with ICIs, nanocarriers can enhance drug accumulation at tumor sites and activate the immune system. Advances in nanotechnology have led to multifunctional nanocarriers capable of co-delivering chemotherapy, immune modulators, and gene-editing tools, supporting effective combination therapies [73].

Future research should focus on optimizing nanocarrier designs for personalized treatment strategies, tailoring therapies to each patient’s tumor characteristics for increased effectiveness and fewer side effects.

4.6 Comparative insights: NDDS in LC versus other diseases

Although the application of NDDS in LC treatment has achieved significant progress, it still faces a series of challenges and opportunities compared to their use in other diseases. For instance, in the field of breast cancer, research on NDDS primarily focuses on HER2-targeted delivery systems to enhance therapeutic specificity and minimize off-target effects [74]. Similarly, in liver cancer studies, efforts are directed toward developing liver-specific nanoparticles to overcome tumor microenvironment barriers and improve therapeutic outcomes [75].

In contrast, LC presents unique therapeutic challenges. These include the need to design delivery systems capable of targeting the pulmonary microenvironment while effectively addressing barriers such as mucus penetration and lung clearance. In this regard, inhalation-based NDDS technologies and advanced active targeting strategies are particularly crucial, as they can significantly enhance local drug concentration while minimizing systemic toxicity [46]. These distinctions highlight the disease-specific nature of NDDS design and underscore the necessity of adopting tailored strategies in LC treatment.

This broader analytical perspective not only helps summarize advancements in LC research but also provides a framework for leveraging insights from other cancer therapies to overcome current limitations and explore innovative therapeutic strategies.

4.7 Limitations and future directions

Despite its valuable contributions, this study has several limitations: (i) The literature search was restricted to the WoSCC due to challenges in standardizing raw data formats from Scopus and PubMed, which prevented a unified analysis. (ii) Only English-language publications were considered, potentially excluding significant non-English research. (iii) Manual standardization was applied to account for variations in terminology, but achieving complete consistency was difficult, potentially resulting in minor discrepancies.

Future research should focus on integrating data from multiple databases, such as Scopus and PubMed, if a method for harmonizing file formats can be developed. This would enable a more comprehensive analysis. Expanding the inclusion criteria to incorporate non-English studies could also offer a broader global perspective. Additionally, leveraging advanced natural language processing tools for data standardization could enhance the accuracy and consistency of bibliometric analyses. Future studies should also investigate the interactions between NDDS and emerging therapies to identify innovative treatment strategies and address the evolving challenges in LC therapy.