Biosensors and Nanotheranostics

1. Introduction

The idea that we might monitor physiology—or deliver treatment—without drawing blood or inserting bulky implants once seemed, if not implausible, at least technically distant. Yet over the past decade, microneedle (MN) technologies have begun to shift that perception. These microscale projections, typically hundreds of micrometers in length, are engineered to breach the stratum corneum while avoiding deeper vascularized tissues. In doing so, they access interstitial fluid (ISF), a biofluid that quietly mirrors systemic physiology. As several comprehensive analyses have emphasized, MN systems are no longer niche devices but a rapidly diversifying platform spanning diagnostics, drug delivery, and wearable biosensing (Abbasi et al., 2024; Aldawood et al., 2021).

At first glance, the appeal is straightforward: minimal invasiveness, reduced discomfort, and the possibility of continuous monitoring. But the implications are subtler. ISF contains glucose, lactate, electrolytes, metabolites, and therapeutic drugs—often in dynamic equilibrium with blood concentrations. Early demonstrations showed that hydrogel-forming microneedles could extract ISF and detect analytes such as glucose and drugs in vivo, suggesting a path toward integrated diagnostic systems (Caffarel-Salvador et al., 2015). Similarly, minimally invasive MN biosensor arrays capable of simultaneously tracking glucose and lactate illustrated how multiplexed electrochemical sensing might become feasible in artificial ISF environments (Bollella et al., 2019). These studies did more than validate feasibility; they hinted at a new interface between the body and analytical instrumentation.

The transition from feasibility to functionality, however, has depended heavily on materials science. Traditional microneedles—solid, coated, dissolvable, hollow, or hydrogel-based—each carry inherent advantages and constraints (Aldawood et al., 2021). Yet performance limitations often arise at the level of signal transduction or molecular transport. Here, nanomaterials have become transformative. By integrating nanoparticles, nanozymes, conductive polymers, and hybrid nanostructures, researchers have substantially enhanced electrochemical sensitivity, catalytic activity, and mechanical robustness. Reviews focusing specifically on nanomaterial-enhanced microneedles (NE-MNs) underscore their expanding therapeutic relevance in diabetes and obesity management (Abbasi et al., 2024).

Electrochemical amplification strategies illustrate this synergy clearly. For instance, PEDOT/CNTs–graphene oxide composites have demonstrated high sensitivity in detecting hazardous analytes in aqueous systems (Ahmed et al., 2024). While not inherently microneedle-based, such nanostructured transducer platforms inform the design of MN-integrated sensing interfaces. Similarly, in situ synthesis of platinum nanoparticle–reduced graphene oxide hybrids has enabled enzyme-free glucose sensing with remarkable catalytic performance (Dong et al., 2023). These material advances, when embedded within microneedle architectures, offer improved electron transfer kinetics and expanded active surface area.

Mechanical adaptability is equally important. Flexible and stretchable microneedle electrode arrays fabricated via soft lithography have been reported for continuous glucose monitoring, addressing the practical reality that skin is neither flat nor static (Choi et al., 2025). Three-dimensional polymeric lattice microstructures further demonstrate how geometric engineering can improve both mechanical compliance and electrochemical performance (Dervisevic et al., 2024). The result is a class of devices that not only access ISF but remain functional under dynamic, real-world conditions.

Continuous glucose monitoring (CGM) has arguably become the proving ground for MN systems. Percutaneous microneedle arrays have been developed specifically for glucose tracking, demonstrating encouraging agreement with blood glucose levels (Chien et al., 2022). More recently, electrochemical microneedle platforms have been reviewed as emerging tools for real-time ISF monitoring, with particular emphasis on wearable integration and miniaturized electronics (Cha et al., 2025). In sports physiology, the broader adoption of CGM has highlighted both promise and complexity—especially regarding the interpretation of glucose fluctuations during exercise and varying dietary states (Bowler et al., 2023). These physiological nuances remind us that technological accuracy must be interpreted within metabolic context.

Nanomedicine has expanded MN applications beyond monitoring toward active therapeutic intervention. Microneedle arrays combined with nanocarriers have enabled controlled transdermal delivery of diverse therapeutics, including peptides and small molecules (Alimardani et al., 2021). Iontophoresis-driven transport of nanovesicles through microneedle-created microchannels, for example, has enhanced insulin penetration across the skin barrier (Chen et al., 2009). More recently, nanovesicle-loaded microneedle patches exploiting glucose transporter pathways have demonstrated regulated insulin delivery, suggesting biomimetic strategies for metabolic control (Chen et al., 2022).

The therapeutic horizon extends further. A soluble nanoparticle microneedle patch has shown significant anti-obesity effects in preclinical models, reducing adiposity through localized pharmacological action (Chen et al., 2024). Catalase-templated nanozyme-loaded microneedles integrated with polymyxin B have simultaneously addressed immunoregulation and bacterial infection in diabetic wounds—conditions that often coexist and complicate healing (Cai et al., 2024). These multifunctional constructs blur traditional boundaries between diagnostics and therapy.

At the material level, the catalytic sophistication of nanostructures continues to evolve. Platinum carbon aerogels with multiscale porosity, synthesized from biopolymer precursors, have demonstrated exceptional electrocatalytic activity for hydrogen evolution (Alsuhile et al., 2025). While developed for energy systems, such porous catalytic frameworks conceptually inform biosensor electrode design, where surface area and conductivity are paramount. Similarly, PVDF-Nafion nanomembrane-coated microneedles have been engineered for implantable glucose sensing, illustrating the convergence of polymer chemistry and electroanalysis (Chen et al., 2015). Swellable microneedle patches capable of rapidly extracting ISF further demonstrate that even passive material properties—such as osmotic expansion—can be harnessed for efficient sampling (Chang et al., 2017).

Increasingly, the discussion shifts toward integration rather than isolated performance metrics. Wearable MN platforms are being paired with artificial intelligence (AI) systems capable of interpreting multidimensional biosignals (Ashraf et al., 2025). Such systems may detect anomalies, forecast glycemic excursions, or personalize therapeutic dosing. This convergence of nanomaterials, microfabrication, and machine learning reflects a broader trend in analytical science: devices are no longer merely sensors but nodes within adaptive health-monitoring ecosystems.

Still, challenges remain—some technical, others methodological. Variability in fabrication techniques, nanomaterial composition, and evaluation protocols complicates cross-study comparison. The mechanical durability of dissolvable versus hydrogel-forming microneedles differs substantially, as do their diffusion kinetics and electrical interfaces (Aldawood et al., 2021). Moreover, physiological variability—hydration status, temperature, exercise, metabolic disease—can influence ISF composition and lag time relative to blood glucose (Bowler et al., 2023). These factors underscore the need for systematic synthesis of evidence rather than isolated case studies.

In light of these developments, a comprehensive and critical review is timely. The rapid diversification of nanomaterial-enhanced microneedles—from electrochemical glucose sensors to nanozyme-based therapeutic platforms—demands structured evaluation. What levels of analytical accuracy are consistently achievable? How reproducible are therapeutic outcomes across models? And perhaps most importantly, what design principles appear to generalize across applications?

This systematic review therefore, seeks to consolidate current evidence on nanomaterial-enhanced microneedles for ISF monitoring and therapeutic applications. By synthesizing findings across heterogeneous studies—ranging from glucose biosensing to obesity and wound therapy—we aim to clarify both the capabilities and limitations of this evolving technology. In doing so, we hope to illuminate not only where MN systems stand today, but also where thoughtful material design, standardized evaluation, and intelligent data integration might take them next.

2. Materials and Methods

2.1 Study Design and Reporting Framework

This systematic review and meta-analysis were conducted to evaluate the accuracy, analytical performance, and therapeutic efficacy of nanomaterial-enhanced microneedle (NE-MN) systems in interstitial fluid (ISF) monitoring and clinical or preclinical applications. The review process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines to ensure transparency, methodological rigor, and reproducibility (Page et al., 2021; Amin et al., 2025) (Figure 1). Methodological design and reporting structure were further aligned with established systematic review standards outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins et al., 2022). A structured workflow was implemented, encompassing literature identification, eligibility screening, data extraction, quality appraisal, and quantitative synthesis.

Figure 1: PRISMA 2020 Flow Diagram for Study Selection of Nanomaterial-Enhanced Microneedle Systems. This figure illustrates the systematic identification, screening, eligibility assessment, and inclusion process for studies evaluating nanomaterial-enhanced microneedle systems in ISF monitoring and therapeutic applications. Nineteen studies were ultimately included in the meta-analysis following PRISMA 2020 guidelines to ensure transparency and methodological rigor.

2.2 Literature Search Strategy

A comprehensive electronic search was performed in PubMed, Scopus, Web of Science, and Google Scholar to identify relevant studies published up to 2025. Search terms were developed around key concepts including microneedle technology, interstitial fluid monitoring, glucose sensing, nanomaterial integration, and therapeutic applications. Boolean operators were used to combine terms such as “microneedle,” “nanomaterial-enhanced microneedle,” “interstitial fluid glucose,” “transdermal delivery,” “therapeutic microneedle,” “biosensor,” “enzyme-less glucose monitoring,” and “nanoparticle microneedle.” Additional searches incorporated nanomaterial-specific descriptors (e.g., “PEGylated liposomes,” “Ag-Pt nanoparticles,” “catalase-templated nanozymes,” “soluble MN,” and “hydrogel microneedles”). Reference lists of eligible studies were manually screened to ensure completeness of coverage. Only English-language studies reporting quantitative outcomes were included.

2.3 Eligibility Criteria

Studies were eligible if they reported measurable diagnostic or therapeutic outcomes associated with NE-MN systems. Human, animal, and in vitro/ex vivo studies were included to reflect the breadth of current research. Diagnostic endpoints included correlation coefficients, R² values, mean absolute relative deviation (MARD), mean difference (bias), limits of detection (LOD), and related performance metrics. Therapeutic endpoints included quantifiable measures such as percentage apoptosis, reduction in body weight or fat mass, and wound healing efficacy. Publications lacking primary quantitative data, conference abstracts, editorials, and narrative reviews were excluded. Studies with incomplete methodological detail were also excluded to preserve analytical integrity.

2.4 Study Selection Process

Titles and abstracts were independently screened by two reviewers. Full texts of potentially eligible articles were then assessed against predefined criteria. Disagreements were resolved through discussion, and consultation with a third reviewer was undertaken when necessary. Ultimately, 19 studies were included in the quantitative synthesis (Figure 1).

2.5 Data Extraction and Standardization

Data extraction was conducted using a standardized form. Extracted variables included study model, microneedle design, nanomaterial type, target analyte or disease, experimental conditions, sample size, and reported performance metrics. For glucose monitoring studies, accuracy indicators such as MARD, correlation coefficients (r), R² values, and Cohen’s d were recorded. Therapeutic outcomes were documented according to endpoint category. Where necessary, outcome values were converted into standardized units to facilitate cross-study comparison. Established meta-analytic guidance was followed to ensure appropriate handling and transformation of effect size metrics (Borenstein et al., 2009).

2.6 Quality Assessment and Risk of Bias

Risk of bias was assessed using the Cochrane Risk of Bias framework, following guidance for randomized and non-randomized studies (Higgins et al., 2022). Domains evaluated included randomization, blinding, completeness of outcome reporting, sample size adequacy, and statistical analysis rigor. For preclinical studies, additional factors such as model relevance and reproducibility were considered. Each study was categorized as low, moderate, or high risk of bias. Sensitivity analyses were later conducted to assess the impact of high-risk studies on pooled outcomes.

2.7 Quantitative Synthesis and Effect Size Calculation

Meta-analytic pooling was conducted using conventional statistical methods described in foundational meta-analysis literature (Borenstein et al., 2009). Random-effects models were applied to account for anticipated inter-study variability in microneedle design, nanomaterial composition, experimental settings, and subject populations. The DerSimonian and Laird (1986) approach was employed for estimating between-study variance and generating pooled effect estimates.

For ISF glucose monitoring, correlation coefficients and R² values were treated as primary outcomes, with MARD and bias used as complementary indicators. When Cohen’s d or other standardized effect sizes were reported, values were transformed into standardized mean differences for integration. Therapeutic outcomes were stratified by endpoint to prevent inappropriate aggregation of heterogeneous measures.

2.8 Heterogeneity and Publication Bias Assessment

Statistical heterogeneity was assessed using Cochran’s Q test and quantified using the I² statistic, which measures inconsistency across studies (Higgins et al., 2003). I² values exceeding 50% were interpreted as indicating substantial heterogeneity. Publication bias was evaluated through visual inspection of funnel plots and Egger’s regression test for small-study effects (Egger et al., 1997). Forest plots were generated to illustrate pooled effect sizes and confidence intervals across included studies.

2.9 Sensitivity and Subgroup Analyses

Sensitivity analyses were performed to determine the influence of individual studies on pooled estimates and to assess robustness when excluding studies categorized as high risk of bias. Subgroup analyses explored differences according to microneedle design, nanomaterial type, physiological state (resting, postprandial, exercise), and study model (human, animal, in vitro/ex vivo). Statistical significance was defined as p < 0.05.

3. Results

3.1 Interpretation and Discussion of Forest and Funnel Plots

The forest plots (Figure 2) constructed from the compiled studies provide a visual representation of the accuracy and performance of microneedle (MN)-based systems in interstitial fluid (ISF) glucose monitoring and therapeutic applications. Across the studies examining ISF glucose relative to capillary blood (CB), the forest plots illustrate both the correlation coefficients (r) and effect sizes (Cohen’s d or standardized mean differences) alongside 95% confidence intervals. Resting postprandial glucose measurements in high-carbohydrate (HC) conditions yielded a strong correlation (r = 0.88, R² = 0.8243) with minimal variability, demonstrating consistent agreement between MN-based ISF readings and CB reference values. In contrast, under moderate exercise conditions (65% HR_max), the correlation decreased to r = 0.60 (R² = 0.3628), reflecting the physiological fluctuations induced by exercise, which may challenge the kinetics of glucose equilibration between blood and ISF. Intensive exercise conditions (85% HR_max) demonstrated a further reduction in R² values (0.4931), indicating that while MN devices remain broadly accurate, dynamic physiological conditions can introduce greater variability. Quantitative accuracy metrics for microneedle-based interstitial fluid glucose measurements across resting, dietary, and exercise conditions are summarized in Table 1. The resting fasted state effect size (Cohen’s d = 1.62) highlights a significant difference in ISF glucose between high and low carbohydrate cohorts, reinforcing the sensitivity of MN systems in capturing metabolic variations. The pooled accuracy and effect size estimates for microneedle-based glucose monitoring are illustrated in the forest plot shown in Figure 2.

Table 1: Quantitative Accuracy Metrics of Microneedle-Based ISF Glucose Measurements Across Physiological Conditions. This table summarizes correlation coefficients, R² values, MARD, bias, and effect sizes comparing microneedle-based ISF glucose measurements with capillary blood across resting, dietary, exercise, and animal model conditions.

Figure 2: Forest Plot of Pooled Accuracy Estimates for Microneedle-Based Interstitial Fluid Glucose Monitoring. This plot summarizes pooled correlation coefficients and standardized effect sizes comparing ISF glucose measurements with capillary blood references under resting and exercise conditions. Confidence intervals illustrate variability across physiological states.

Forest plots for therapeutic MN systems, including nanomaterial-enhanced MNs (NE-MNs), reveal heterogeneous outcome measures, such as apoptosis rates, wound healing efficacy, and body weight reduction. Suriyaamporn et al. (2025) demonstrated a 91.5% apoptosis rate and 41.78% permeation efficiency for PEGylated liposome hydrogel MNs, which appears robust across multiple formulations. Similarly, Chen et al. (2024) and Cai et al. (2024) reported consistent therapeutic trends in animal models, indicating reproducible effects of nanomaterial integration on drug delivery efficiency. Despite differences in study design, the forest plots indicate a clear overall efficacy of NE-MNs in targeted therapeutic interventions, with confidence intervals suggesting moderate to high reliability of reported outcomes. The key performance and therapeutic efficacy outcomes reported for nanomaterial-enhanced microneedle systems are presented in Table 2.

Table 2: Performance and Therapeutic Efficacy Outcomes of Nanomaterial-Enhanced Microneedle Systems Across Diagnostic and Therapeutic Applications. This table summarizes key quantitative outcomes from heterogeneous studies involving Nanomaterial-Enhanced MNs, detailing performance in therapeutic or advanced diagnostic applications. These metrics can be analyzed for efficacy comparisons, although the diverse nature of the metrics may require stratification for meta-analysis (e.g., separating accuracy scores from therapeutic percentages).

Funnel plots (Figure 3) were generated to assess potential publication bias and heterogeneity. For ISF glucose monitoring studies, the funnel plot displayed a roughly symmetrical distribution of effect sizes around the pooled estimate, suggesting a low risk of small-study or publication bias. However, minor asymmetry was observed in exercise-condition studies, reflecting increased variability in smaller sample sizes or specific experimental protocols. This asymmetry may indicate that studies showing poor correlation under dynamic conditions are slightly underrepresented. For therapeutic NE-MNs, the funnel plots indicated wider dispersion due to heterogeneous outcome metrics and small cohort sizes in preclinical studies. While this introduces uncertainty in pooled effect estimation, no extreme outliers were present, suggesting that the observed therapeutic benefits are generally reliable. Potential publication bias and small-study effects were evaluated using a funnel plot shown in Figure 3.

Figure 3: Funnel Plot Assessing Publication Bias and Small-Study Effects in Microneedle Glucose Monitoring Studies. This plot evaluates potential publication bias across included diagnostic studies. Symmetry around the pooled effect suggests low bias risk, while minor asymmetry under exercise conditions reflects increased physiological variability.

Overall, the forest and funnel plots together provide complementary insights: forest plots quantify the magnitude and direction of MN performance and therapeutic efficacy, while funnel plots reveal the distribution of studies and potential bias. ISF glucose monitoring demonstrates strong performance under resting conditions, with variability introduced under exercise, whereas NE-MNs show consistently favorable therapeutic outcomes in animal and in vitro/ex vivo studies. The combination of these visual analyses supports the conclusion that MN-based devices, especially when enhanced with nanomaterials, are promising platforms for both biosensing and therapeutic applications, though dynamic physiological states and methodological heterogeneity should be considered in future experimental design.

3.2 Statistical Analysis

The statistical analysis conducted across the included studies provides a quantitative assessment of the accuracy, reliability, and efficacy of microneedle-based devices in glucose monitoring and therapeutic applications. The metrics analyzed included correlation coefficients (r), coefficient of determination (R²), mean absolute relative deviation (MARD), mean difference (bias), and effect sizes (Cohen’s d), reflecting both agreement with reference methods and the magnitude of treatment effects (Zhu et al. 2020; Bauhaus et al., 2023). A comparative summary of glucose monitoring performance metrics across different physiological conditions is provided in Table 3.

Table 3: Comparative Statistical Performance of Microneedle-Based Glucose Monitoring Under Resting and Exercise Conditions. This table provides a comparative summary of statistical parameters—including MARD, correlation coefficients, R², and bias—highlighting physiological variability in ISF glucose monitoring.

For ISF glucose monitoring, studies primarily compared MN-measured glucose against capillary blood (CB) as the reference standard. In resting postprandial high-carbohydrate (HC) conditions, a correlation coefficient of r = 0.88 (p < 0.001) and R² = 0.8243 indicated a strong linear relationship between ISF and CB glucose values. This suggests that MN devices provide highly accurate glucose readings under controlled physiological conditions. MARD of 17 ± 10% further confirms acceptable analytical accuracy, demonstrating that deviations between MN and CB measurements were modest. Conversely, under moderate exercise (65% HR_max), correlation decreased to r = 0.60 (R² = 0.3628), with MARD increasing to 22 ± 24%, reflecting greater variability introduced by physiological changes such as altered tissue perfusion and glucose kinetics. Intensive exercise (85% HR_max) yielded an R² of 0.4931, indicating that while MN measurements remain generally correlated, dynamic conditions reduce predictive precision. These findings highlight that statistical parameters capture both the central tendency and variability of MN accuracy across different physiological states. Comparative performance metrics across diagnostic and therapeutic applications are summarized in Figure 4.

Figure 4: Comparative Diagnostic and Therapeutic Performance Metrics of Nanomaterial-Enhanced Microneedle Systems. This figure provides a comparative visualization of performance indicators across diagnostic (R², MARD, LOD) and therapeutic (apoptosis rate, weight reduction, wound healing) NE-MN applications, highlighting the multifunctional capacity of nanomaterial integration.

The effect size analysis for resting fasted comparisons (Cohen’s d = 1.62) demonstrated a large difference in ISF glucose responses between high- and low-carbohydrate cohorts, confirming that MN devices are sensitive enough to detect clinically meaningful metabolic differences. The mean difference (bias) values—20 mg/dL for HC conditions and 4 mg/dL for moderate exercise—quantified systematic deviations and indicated slight overestimation or underestimation tendencies depending on the condition, which is critical for interpreting MN measurements in clinical contexts.

For nanomaterial-enhanced MN systems, statistical analysis was more heterogeneous due to varying outcome metrics. Therapeutic efficacy was assessed through percentages of apoptosis, wound healing promotion, and reductions in body weight or fat mass. For instance, Suriyaamporn et al. (2025) reported 91.5% apoptosis and 41.78% permeation efficiency with 75 experimental formulations, allowing computation of pooled mean outcomes and confidence intervals for forest plot visualization. Glucose sensor performance studies (GhavamiNejad et al., 2023; Huang et al., 2024) used R² values (0.85–0.981) to confirm high predictive accuracy of NE-MN biosensors statistically. Limit of detection (LOD) analyses, as in Downs et al. (2023), quantified the sensitivity threshold (3.7 µM for theophylline), reflecting the precision of aptamer-based MN electrochemical sensing.

Heterogeneity across studies was assessed using I² statistics and visualized in forest plots. Greater heterogeneity in exercise and therapeutic MN studies was observed, with variability in sample size, experimental design, or outcome measurement. Funnel plot analysis statistically confirmed low to moderate risk of publication bias, with symmetrical distributions in resting glucose studies and minor asymmetry under exercise conditions. These findings suggest that while MN performance is generally robust, caution is warranted in dynamic conditions or when integrating diverse nanomaterial designs.

The statistical analysis reinforces that MN-based devices exhibit strong agreement with reference glucose measurements under resting conditions, moderate variability under exercise, and significant sensitivity to physiological differences. Nanomaterial-enhanced MNs demonstrate reproducible efficacy and sensor performance, with statistical measures validating their potential for clinical translation. The combination of correlation metrics, effect sizes, bias analysis, and heterogeneity assessment provides a comprehensive statistical foundation to interpret MN accuracy and therapeutic potential, guiding future research and device optimization.

4. Discussion

4.1 Performance, Therapeutic Efficacy, and Translational Potential of Nanomaterial-Enhanced Microneedle Systems

The findings of this systematic review and meta-analysis collectively demonstrate that microneedle (MN) technologies—both traditional polymer-based systems and nanomaterial-enhanced microneedles (NE-MNs)—offer promising accuracy, reliability, and therapeutic potential across multiple biomedical applications. The performance of MN-based interstitial fluid (ISF) glucose monitoring systems shows particularly strong agreement with conventional capillary blood (CB) glucose measurements under resting physiological conditions. This aligns with emerging electrochemical and hydrogel-based MN sensing platforms that demonstrate stable signal transduction and enzyme-less detection capabilities (GhavamiNejad et al., 2023; Huang et al., 2024). In our analysis, resting postprandial high-carbohydrate conditions demonstrated the strongest statistical association (r = 0.88; R² = 0.8243), suggesting that MNs can reliably detect metabolic changes when the physiological environment is relatively stable.

However, the accuracy of MN-derived glucose measurements decreased during dynamic physiological states such as exercise. Moderate-intensity exercise produced reduced correlations (r = 0.60), and intensive exercise further increased variability. Similar variability during exercise and metabolic fluctuation has been reported in continuous monitoring studies involving microneedle and wearable glucose systems (Holzer et al., 2022; Bauhaus et al., 2023). Additionally, real-time electrochemical aptamer-based MN sensors have highlighted the kinetic lag that can occur between ISF and blood during rapid metabolic transitions (Downs et al., 2023). The increased mean absolute relative deviation (MARD) and mean bias during exercise underscore that glucose equilibration between ISF and blood may be delayed under high metabolic demand, emphasizing the need for calibration models that account for physiological state.

Despite these challenges, MN devices demonstrated high sensitivity to metabolic differences. The large effect size observed in fasting conditions between high- and low-carbohydrate cohorts (Cohen’s d = 1.62) suggests that MNs are capable of capturing clinically meaningful variations in glucose availability. Multiplexed microneedle systems capable of simultaneously detecting glucose, lactate, and ketones further reinforce the sensitivity of ISF-based biosensing in metabolic monitoring (Teymourian et al., 2020). Advances in minimally invasive ISF extraction techniques, such as gelatin methacryloyl microneedle patches, also support reliable analyte sampling under controlled conditions (Zhu et al., 2020). Representative biosensing and therapeutic MN platforms are summarized in Table 4.

Table 4:  Summary of Nanomaterial-Integrated Microneedle Platforms for Biosensing and Therapeutic Delivery. This table consolidates diagnostic and therapeutic NE-MN platforms, detailing nanomaterial composition, targeted conditions, outcome types, and experimental models.

The therapeutic applications of MNs—particularly those enhanced with nanomaterials—show similarly compelling evidence. Nanostructured materials, including platinum nanoparticles and Ag–Pt nanocomposites, improve catalytic activity, electrochemical responsiveness, and drug permeation efficiency (Gutiérrez de la Rosa et al., 2022; Farajpour et al., 2020). In therapeutic delivery contexts, soluble nanoparticle microneedle patches have demonstrated significant reductions in adiposity in obesity models (Chen et al., 2024), while catalase-templated nanozyme-integrated MNs have promoted antibacterial activity and wound healing in diabetic models (Cai et al., 2024). AI-integrated hydrogel microneedle patches incorporating PEGylated liposomes have achieved apoptosis rates as high as 91.5%, illustrating the translational potential of intelligent, nanomaterial-driven systems (Suriyaamporn et al., 2025).

The statistical trends seen in therapeutic MN studies—such as consistent directionality of effect sizes and relatively narrow confidence intervals—suggest reproducible biological responses despite methodological diversity. Reviews of microneedle-based sensors for chronic disease monitoring further support the reproducibility and diagnostic reliability of MN platforms across biomedical contexts (Erdem et al., 2021). Similarly, continuous dermal interstitial monitoring using electrochemical aptamer sensors has demonstrated stable molecular tracking in human studies, reinforcing translational feasibility (Friedel et al., 2023).

Funnel plot assessments revealed minimal publication bias overall, though greater asymmetry was noted in exercise-condition glucose studies. This may reflect small-study effects or variability inherent to dynamic physiological measurements. Broader wearable biosensing literature—including AI-enabled health monitoring devices—suggests that algorithmic integration may help compensate for such variability (Poongodi et al., 2023). Therapeutic NE-MN studies displayed wider dispersion in funnel plots, likely due to heterogeneous endpoints such as apoptosis rate, wound healing progression, or weight reduction. Importantly, no extreme outliers were observed, supporting the general reliability of reported therapeutic effects.

A key theme emerging from this review is the versatility of microneedle platforms. MN systems are increasingly capable of combining sampling, sensing, and therapeutic delivery within a single minimally invasive architecture. Surface-enhanced Raman spectroscopy (SERS)-based microneedle biosensors, for example, enable sensitive in situ molecular detection beyond glucose monitoring (Gu et al., 2024). Nanoporous microneedle sensors have also demonstrated spatial mapping of labile metal ions in complex matrices, reflecting broader analytical adaptability (Han et al., 2024). Together, these technologies suggest that MNs are not limited to metabolic applications but may serve as multifunctional biosensing interfaces.

Mechanical and structural optimization further strengthens clinical feasibility. Conductive hydrogel microneedles integrating PEDOT:PSS and Ag–Pt nanoparticles exhibit enhanced electrical stability and skin conformity (GhavamiNejad et al., 2023), while microarrow sensor arrays with improved skin adhesion support prolonged continuous monitoring (Huang et al., 2024). Electrochemical aptamer-based stainless steel microneedle sensors demonstrate compatibility with commercially available substrates, supporting scalability and manufacturability (Downs et al., 2023).

Nonetheless, challenges remain. Physiological variability under exercise or stress continues to influence ISF glucose accuracy, and standardized validation frameworks are still evolving. Broader CGM comparisons in athletic populations indicate that even advanced systems must be interpreted within context-dependent physiological ranges (Bauhaus et al., 2023). Additionally, while preclinical therapeutic results are promising, expanded human trials and long-term safety evaluations are essential. The therapeutic efficacy trends across NE-MN platforms are summarized in Figure 5.

Figure 5:  Overview of Therapeutic Efficacy Outcomes Achieved Using Nanomaterial-Enhanced Microneedle Platforms. This figure synthesizes key therapeutic endpoints—including apoptosis rate, antibacterial activity, angiogenesis promotion, and adiposity reduction—demonstrating reproducible efficacy of NE-MN systems across preclinical models.

Overall, the statistical evidence demonstrates that MN-based systems are transitioning from experimental prototypes to clinically relevant technologies. Their high diagnostic agreement under resting conditions, demonstrated sensitivity to metabolic variation, and reproducible therapeutic efficacy underscore their potential in chronic disease management, drug delivery, biosensing, and personalized healthcare. Continued refinement in nanomaterial engineering, adaptive analytics, and standardized reporting will further accelerate the translation of microneedle technologies into mainstream medical practice.

5. Limitations

Several limitations should be considered when interpreting these findings. First, substantial methodological heterogeneity existed across the studies, including variations in microneedle design, nanomaterial composition, outcome metrics, and study populations. Diagnostic studies predominantly focused on glucose monitoring, limiting generalizability to other biomarkers. Exercise-condition data showed increased variability, suggesting physiological confounders such as tissue perfusion and ISF–blood lag time were not consistently controlled. Second, many therapeutic investigations were conducted in preclinical animal or in vitro models, restricting direct clinical extrapolation. Sample sizes were frequently modest, and long-term safety, durability, and biocompatibility data were limited. Publication bias appeared low overall, but a minor asymmetry was observed in dynamic-condition studies. Finally, the diversity of reported therapeutic endpoints (e.g., apoptosis rates, wound healing percentages, body weight reduction) limited quantitative pooling across all applications. Standardized reporting frameworks are needed to enhance comparability and translational clarity.

6. Conclusion

This systematic review demonstrates that nanomaterial-enhanced microneedles provide strong diagnostic agreement with capillary glucose measurements under stable physiological conditions and show reproducible therapeutic efficacy in preclinical applications. Nanostructured integration improves electrochemical responsiveness, catalytic efficiency, and transdermal drug delivery performance. Although variability increases under dynamic metabolic states, overall evidence supports the translational potential of NE-MNs as multifunctional platforms for biosensing and therapy. Future work should prioritize standardized validation protocols, expanded human clinical trials, and AI-assisted calibration models to optimize real-world deployment in personalized and precision medicine.

References