Neurodegenerative diseases (NDs) comprise a group of progressive disorders characterized by neuronal loss and functional decline, leading to worsening cognitive, behavioral, and/or motor impairments over time [1]. Common NDs include Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington disease (HD). Globally, more than 50 million individuals are affected, and the prevalence is rising with population aging, creating a growing public health and economic burden [2]. Although decades of research have clarified key pathological hallmarks, such as β-amyloid deposition, tau hyperphosphorylation, and α-synuclein aggregation [3,4], most available therapies remain largely symptomatic and do not reliably halt or reverse disease progression. Only a limited number of drugs, including donepezil and levodopa, are approved for clinical use, and their benefits are modest and often constrained by adverse effects. Accordingly, there remains a strong need for therapies that modify disease mechanisms rather than symptoms alone [5,6].

Recent advances in gene editing and stem cell technologies have created new therapeutic possibilities for NDs [7,8]. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system enables precise perturbation of disease-relevant genes and can be used to correct pathogenic variants or modulate aberrant protein expression, including targets such as APP, SNCA, SOD1, and C9orf72. In parallel, induced pluripotent stem cells (iPSCs) can be differentiated into functional neuronal populations, providing a platform for cell replacement strategies. For example, CRISPR-based SOD1 silencing delays motor neuron degeneration in ALS models, and transplantation of iPSC-derived dopaminergic neurons has shown potential to improve motor outcomes in clinical studies of PD [9]. Notably, the convergence of these approaches is becoming an active research direction. The Cas9nVQR editing tool can efficiently modulate gene dosage in human iPSCs and has been reported to ameliorate AD-related phenotypes, including amyloid-β (Aβ) secretion and tau hyperphosphorylation [10]. Gene editing may also be applied to improve graft survival and functional engraftment by reducing immune rejection after transplantation [11]. However, key challenges remain, including off-target editing, tumorigenic risk of stem cell–derived products, and safe and efficient delivery in vivo. Addressing these barriers will be essential for clinical translation.

Bibliometric analysis applies quantitative methods to published literature to map the knowledge structure and research dynamics within a field. Using tools, such as CiteSpace, VOSviewer, and HistCite, bibliometrics can identify influential contributors and core documents, track emerging topics, and evaluate scholarly impact. It can also reveal collaboration networks and cross-disciplinary opportunities, thereby informing more strategic allocation of research efforts and resources. In addition, bibliometric evidence can help policymakers understand field trajectories and support evidence-based decision-making [12-14]. In NDs, prior bibliometric studies have focused on selected diagnostic and therapeutic topics [15,16]. However, gene editing and stem cell therapy represent rapidly expanding and increasingly intersecting frontiers, and a systematic bibliometric assessment of their progress, technical barriers, and translational trajectories in NDs remains lacking. Therefore, we performed a bibliometric and visual analysis of global research on gene editing and stem cell therapy for NDs from 2005 to 2024. By integrating publication trends, institutional collaboration networks, co-citation clustering, and keyword burst detection, this study aims to define the field’s intellectual landscape, highlight evolving hotspots, and identify major bottlenecks limiting clinical translation [17].

The treatment of NDs is at a critical inflection point, with gene editing and stem cell therapy increasingly converging as translational strategies. To our knowledge, this study is the first bibliometric analysis to systematically map the global research landscape and emerging trends in this field. Over the past 2 decades, annual publication output increased in a stepwise fashion and entered a clear acceleration phase after 2016. This shift likely reflects several enabling advances in gene and cell therapy. For example, the rAAV2-retro variant, which has been generated through AAV capsid engineering, can efficiently access projection neurons via retrograde transport, improving gene delivery performance [28]. In parallel, iPSCs became essential for disease modeling, and MSCs engineered to overexpress brain-derived neurotrophic factor (BDNF) improved outcomes in HD mouse models [29]. Together, these developments likely contributed to sustained growth from 2016 onward. High-impact outputs in this area also show recognizable milestone patterns. The local citation peak in 2008 (TLCS=413; TLCS/TGCS=13.14%) may relate to studies reporting that MSC transplantation can prolong survival, reduce neuroinflammation, and improve motor neuron function in ALS mouse models [30,31]. In contrast, the global citation peak in 2017 (TGCS=9092) likely reflects broad uptake of the widely cited review “Parkinson disease” in Nature Reviews Disease Primers (2017), which synthesized gene therapy targets and vectors as well as the trajectory and current status of stem cell–based strategies in PD [32]. These peaks appear to align with 2 key stages of field development: proof-of-concept experimental validation and consolidation of translational pathways.

At the country level, the United States maintains a dominant position in publication output as well as in the TLCS and TGCS, and the top 5 institutions are all based in the United States. The Boston area, anchored by Harvard University and Massachusetts General Hospital, exemplifies a “basic-to-clinical” collaborative ecosystem, where geographic proximity may facilitate high-frequency interaction and accelerate translation. The sustained US advantage likely reflects multiple reinforcing factors. Long-term and stable research and development investment provides resilience for high-risk, long-cycle research and supports continuity in key directions. In addition, policy and institutional infrastructure (eg, federal funding mechanisms, evaluation systems, open science practices, and industry-academia translation pathways) may improve efficiency across the pipeline—from project initiation to dissemination—thereby strengthening both output and impact. Finally, the centrality of US institutions within international collaboration networks increases access to high-impact consortia and may amplify visibility and downstream citation performance.

China and India contribute substantial publication volume, but their per-paper citation impact remains comparatively low (China: 248 articles; 29.01 citations per article; India: 110 articles; 19.63 citations per article). Collaboration structure may partly explain this gap. China’s collaboration intensity with Western countries remains far below that of the United States (Figure 3B), and India appears more peripheral in the international network, potentially limiting exchange and dissemination. Journal distribution may also contribute. As shown in Table 4 and Figure 6A, outputs from these countries more often appear in high-volume journals with lower field-specific influence, whereas representation in specialty high-impact venues, such as Molecular Therapy, remains limited. In addition, keyword evolution (Figures 7 and 8) suggests that research from these countries may concentrate more heavily on applied and translational clusters, while fewer outputs appear to define foundational, concept-setting advances that often drive long-term citation accumulation. Collectively, these patterns suggest that increasing influence will require deeper integration into high-impact international networks and more sustained investment in originality and frontier research.

At the same time, our data suggest a complementary global innovation landscape. The United States shows broad leadership with strong representation in foundational and early-translational clusters, such as novel AAV engineering and first-in-human studies, consistent with its network position and presence in high-impact journals [33]. In contrast, publication growth from countries, such as China and India, aligns more strongly with applied technology clusters, including nanoparticle delivery systems and stem cell transplantation protocols [34]. European contributors, including Germany and the United Kingdom, show sustained depth in mechanistic clusters, such as oxidative stress and protein aggregation, reflecting enduring strengths in fundamental biomedical science [35]. These patterns argue for collaboration models that pair mechanistic depth, platform engineering, and clinical execution. Institutions seeking higher impact may benefit from long-term partnerships with leading laboratories through co-designed projects and joint publication strategies, alongside deliberate targeting of field-leading specialty journals and sustained investment in frontier directions.

Our co-citation and keyword analyses highlight recurring focal areas, including “adeno-associated virus,” “nanoparticles,” “blood-brain barrier,” and “marrow stromal cells.” AAV vectors remain central tools due to relatively low immunogenicity, broad tropism, and stable long-term transgene expression [36]. We also identified clusters, such as “lentivirus” and “siRNA.” Lentiviral vectors can enable durable gene expression through genomic integration and provide relatively large cargo capacity for platforms such as CRISPR/Cas9 or neurotrophic factor genes [37,38]. Small interfering RNA (siRNA) can silence pathogenic genes through RNA interference and may also complement gene-editing strategies by modulating target expression or reducing unintended activity [39]. However, clinical translation remains constrained by 2 major bottlenecks [40]. First, BBB penetration is often insufficient in humans, despite robust performance in some animal studies. Second, neutralizing antibodies against AAV can reduce transduction efficiency and may contribute to treatment failure, while immune-evasion strategies remain comparatively underdeveloped. Recent progress in surface-modified and targeted nanoparticles has improved BBB delivery [41]. In our analyses, “nanoparticles” emerged as both a persistent focus and a growing frontier. Nanoparticles (1‐100 nm) can be engineered (eg, using rabies virus glycoprotein peptides or lactoferrin) to facilitate BBB transport; protect payloads, such as AAV and siRNA; and potentially influence stem cell survival and differentiation [42,43]. Encapsulating AAV within lipid nanoparticles, for example, has been reported to enhance vector stability and in vivo penetration through optimization of lipid composition and structure [44]. These advances underscore the promise of integrating material science with vector biology to improve delivery and the therapeutic index.

Another prominent cluster was “autophagy,” a cellular quality-control pathway that clears misfolded proteins and damaged organelles. Enhancing autophagy is an attractive therapeutic direction, but precise bidirectional control remains challenging because excessive activation risks degrading essential proteins [45]. MSCs and MSC-derived extracellular vesicles also remain highly visible in the literature. The burst term “marrow stromal cells” supports sustained attention to MSC-based strategies. Bone marrow–derived MSCs can support neural repair through the secretion of neurotrophic factors and immunomodulatory effects [46]. Human MSCs engineered to overexpress BDNF improved outcomes in HD mouse models [29,47]. Laromestrocel, an allogeneic bone marrow–derived MSC product from young healthy donors, has shown encouraging findings in AD, including reduced rates of whole-brain volume loss and hippocampal atrophy, without amyloid-related imaging abnormalities during treatment [48]. As a cell-free alternative, MSC-derived exosomes are emerging as nanoscale carriers capable of delivering therapeutics to the brain, supporting Aβ clearance and neuroprotection [49]. MSC-derived exosomes have also been reported to localize to inflamed brain regions and to be taken up by neurons, suggesting potential for targeted delivery [50]. The recent emergence of “open label” indicates that clinical translation is advancing but still concentrated in early validation. Consistent with this, many highly cited clinical studies in this field are phase I open-label trials. While open-label designs are practical for early exploration, definitive efficacy requires subsequent confirmation in larger randomized, double-blind controlled studies [24-27]. Beyond vector-related barriers, translation also faces platform-wide challenges: nanoparticle safety and long-term stability in humans remain incompletely defined; MSC survival and integration after transplantation are often limited; gene editing carries the risk of off-target effects; and stem cell–based approaches raise concerns regarding tumorigenicity and immune reactions. Finally, many trials remain limited by a small sample size and a short follow-up, underscoring the need for larger cohorts and longer-term surveillance to establish durability and rare safety signals.

Our keyword clustering further resolved thematic dimensions beyond tools and cells. These included disease entities and mechanisms (eg, oxidative stress, mutant huntingtin, AD, and ALS), gene-editing and gene-therapy platforms (CRISPR/Cas9, AAV, and AADC), stem cell and cell therapy strategies (MSCs, neural stem cells, and transplantation), delivery paradigms (CED and BBB), and experimental models and neuroprotection-related themes (mouse models and nerve growth factor). Oxidative stress reflects cellular injury driven by excessive reactive oxygen and nitrogen species, and interventions that neutralize reactive oxygen species remain under active exploration, although deeper mechanistic work is still needed to guide therapeutic development. CRISPR/Cas9 enables precise genome manipulation [51], and AADC gene therapy has shown translational potential in PD, although dose optimization and immunogenicity remain important challenges. Stem cell therapy offers multitarget potential but continues to face constraints in standardized manufacturing, delivery efficiency, and long-term safety [52-56]. Delivery remains a central determinant of success: CED can improve distribution within the central nervous system and offers a strategy to address BBB-associated constraints [57,58]. Animal models remain essential, but differences between rodents and humans, particularly BBB properties and lifespan, can contribute to translational inconsistency. Clinical studies of neurotrophic factors, such as nerve growth factor, have generally shown safety but limited efficacy in late-stage disease, highlighting the complexity of these interventions [59]. Overall, progress will depend on improving delivery and efficiency, reducing immune barriers, and strengthening safety assessments to support reliable clinical benefit.

The integration of iPSC technology with CRISPR/Cas9 editing remains particularly promising for personalized approaches. Patient-derived iPSCs can mitigate immune rejection concerns while enabling gene correction or targeted modification. In HD, CRISPR/Cas9 correction of CAG-repeat expansions in HTT in patient-derived iPSCs yielded differentiated neurons with improved functional phenotypes [60]. Additionally, iPSCs can differentiate into diverse neural cell types, and when combined with CRISPR/Cas9 technology, they enable the generation of specialized cells tailored for multicell-type ND therapies. In PD treatment, researchers differentiated iPSCs into dopaminergic neurons, applied CRISPR-mediated gene correction, and observed symptom improvement in PD models following transplantation [61]. In AD, neurons or astrocytes can be obtained through differentiation of patient-derived iPSCs, and CRISPR/Cas9 can be used for precise knock-in/out or allele replacement of key risk genes, such as APP, PSEN1/2, and APOE, thereby reversing most phenotypes [62]. In ALS, pathogenic variants around SOD1, C9ORF72, TARDBP, and FUS can be investigated in motor neurons differentiated from iPSCs and their co-culture systems, observing key phenotypes such as RNA metabolism abnormalities, stress granules, axonal transport deficits, and cell nonautonomous damage, as well as using gene correction to validate the causal relationship between phenotypes and mutations [63]. Across multiple ND models, combined iPSC-CRISPR strategies have shown therapeutic benefit with acceptable tolerability and low immunogenicity in animal studies [64].

In the process of transitioning technologies from the laboratory to clinical and industrial applications, ethical considerations and regulatory frameworks often pose more immediate practical bottlenecks, impacting whether new technologies can gain approval, establish trust, and achieve large-scale implementation, in addition to scientific feasibility and engineering maturity. Ethically, it is essential to regulate informed consent, privacy, and data security while ensuring fairness in the risk-benefit balance. In the context of iPSCs and CRISPR, particular attention should be given to evaluating off-target or unintended effects, long-term safety, follow-up requirements, and the protection of vulnerable populations. On the regulatory front, this involves product attributes, quality systems, and the requirements for clinical evidence and risk management, including endpoint settings and long-term safety evaluations. These factors significantly influence research design, data availability, timelines, and costs, ultimately determining the efficiency of translation.

This study has several limitations. First, literature retrieval was restricted to the WoSCC, which may omit journals or regional contributions not indexed in this database. Second, although search terms were refined, omissions cannot be fully excluded. Third, we did not incorporate additional translational indicators, such as patent landscapes.

This study systematically reveals dynamic development trends and research hotspots in gene editing and stem cell therapy for NDs through bibliometric analysis. Global annual publications show stepwise growth, with countries like the United States and Germany making outstanding contributions. However, clinical translation faces challenges, such as low BBB penetration efficiency and immune responses, though emerging approaches like nanoparticle-rabies virus glycoprotein peptide modification and MSC exosomes demonstrate breakthrough potential. Additionally, combined applications of iPSCs and CRISPR/Cas9 gene editing show significant therapeutic promise. The “open label” keyword burst indicates that most studies remain in early validation phases, characterized by small clinical trial samples, short observation periods, and weak evidence levels, necessitating urgent validation of long-term safety and efficacy. Future efforts should prioritize optimizing delivery systems, validating clinical translation, and fostering interdisciplinary research (eg, artificial intelligence–driven AAV capsid design) through dedicated ND funds. Strengthening “basic-clinical-industrial” collaborative networks, enhancing clinical evidence quality, and exploring CRISPR/Cas9-stem cell integration will provide critical pathways to overcoming therapeutic bottlenecks in NDs.