Systematic review of nanoelectronic drug delivery systems advancing technological innovation, clinical integration, and personalized therapy

Nanoelectronic Drug Delivery Systems (NEDDS) represent a transformative convergence of nanotechnology, electronic engineering, and precision medicine. This systematic review critically evaluates the evolution, technological advancements, clinical applications, and prospects of NEDDS in personalized therapy. Guided by the PRISMA framework, a comprehensive synthesis of 135 high-quality, peer-reviewed studies was conducted, incorporating robust quality appraisal using CASP and a modified JBI checklist. Thematic analysis via NVivo identified four central domains: historical development, technological innovation, clinical integration, and safety-regulatory considerations. Key findings reveal that NEDDS enable precision targeting through functionalized carriers, real-time therapeutic monitoring, and dynamic treatment adjustment based on pharmacogenomic data, thereby enhancing efficacy and minimizing adverse effects. Specific applications include implantable nanosensors for continuous glucose monitoring in diabetes management, electroresponsive carriers for on-demand chemotherapy delivery in oncology, and transdermal nanochips for pain modulation. Recent advancements such as AI-driven drug dosing algorithms, wireless feedback-controlled microdevices, and integration with 3D-printed personalized drug reservoirs highlight the growing sophistication of NEDDS. These systems also leverage smart technologies to enhance patient compliance and therapeutic autonomy. Despite these innovations, challenges persist, particularly concerning nanomaterial biocompatibility, ethical data governance, and underdeveloped regulatory infrastructure. The review underscores the urgent need for comprehensive safety evaluations, interdisciplinary collaboration, and streamlined regulatory frameworks to facilitate clinical translation. With strategic innovation and oversight, NEDDS holds immense potential to redefine personalized healthcare by delivering smarter, safer, and more adaptive treatment modalities.

Highlights

• This systematic review synthesizes 135 high-quality, peer-reviewed studies on Nanoelectronic Drug Delivery Systems (NEDDS), providing a comprehensive evaluation of their evolution and future prospects.

• Four core thematic domains were identified: historical development, technological innovations, clinical integration, and safety-regulatory considerations.

• NEDDS offer precision drug targeting, real-time therapeutic monitoring, and dynamic treatment adjustments informed by pharmacogenomic data, leading to enhanced efficacy and reduced adverse effects.

• Representative clinical applications include: Implantable nanosensors for continuous glucose monitoring in diabetes management, Electroresponsive carriers enabling on-demand chemotherapy delivery for oncology treatments, and Transdermal nanochips designed for non-invasive pain modulation.

• Technological advancements feature AI-driven drug dosing algorithms, wireless feedback-controlled microdevices, and 3D-printed personalized drug reservoirs, demonstrating the growing sophistication of NEDDS.

• Integration with smart technologies supports patient compliance, therapeutic autonomy, and personalized treatment strategies.

• Persistent challenges include nanomaterial biocompatibility concerns, ethical and data governance issues, and insufficient regulatory frameworks hindering clinical translation.

• The review emphasizes the need for rigorous safety evaluations, interdisciplinary collaboration, and streamlined regulatory pathways to enable safe and scalable adoption.

• With continued innovation and robust oversight, NEDDS hold significant potential to transform personalized medicine, delivering smarter, safer, and more adaptive therapeutic modalities.

1 Introduction

The convergence of precision engineering and biomedical science has catalyzed a profound transformation in therapeutic delivery, heralding the era of Nanoelectronic Drug Delivery Systems (NEDDS). These systems represent a cutting-edge frontier in personalized medicine, combining the spatial precision of nanotechnology with the responsive intelligence of electronic systems to deliver tailored therapeutic interventions. In contrast to conventional drug delivery platforms, which often rely on passive diffusion and generalized dosing, NEDDS offer real-time, feedback-driven control over the timing, location, and dosage of therapeutics, hallmarks of precision medicine (Hassan et al., 2025; Ugwu et al., 2025). Drug delivery has historically evolved from rudimentary and empirical practices to sophisticated, targeted methodologies aimed at maximizing therapeutic index while minimizing off-target effects. This evolution has been driven in part by the growing complexity of diseases such as cancer, neurodegenerative disorders, and multidrug-resistant infections, which demand a higher degree of therapeutic specificity and adaptability than traditional approaches can offer (Ongesa et al., 2025). The limitations of conventional systems, including poor bioavailability, systemic toxicity, and inefficient targeting, have necessitated a new generation of smart delivery technologies.

Nanotechnology has emerged as a transformative solution to these challenges, enabling the engineering of nanoparticles, liposomes, micelles, and dendrimers that can encapsulate and release drugs in a controlled manner. These nanoscale carriers can be functionalized for tissue-specific targeting, improved solubility, and enhanced cellular uptake. However, the integration of nanoelectronics elevates these capabilities further by embedding sensors, actuators, microprocessors, and wireless communication modules within drug delivery systems. This hybrid architecture allows NEDDS not only to sense and respond to physiological conditions but also to be externally programmed or autonomously modulated based on real-time biological feedback (Thakur and Agrawal, 2015; Hu et al., 2018). NEDDS serve as intelligent therapeutic platforms capable of dynamic dose adjustment, localized drug release, and continuous physiological monitoring, aligning perfectly with the goals of personalized medicine. Personalized medicine aims to tailor treatment regimens according to an individual’s genetic, epigenetic, metabolic, and environmental characteristics. In this context, NEDDS bridges a critical technological gap by providing the necessary interface between complex biological systems and precision-engineered control mechanisms (Date et al., 2010). For instance, in oncology, NEDDS can deliver chemotherapeutics directly to tumor sites while continuously monitoring pH, temperature, or biomarker concentrations to optimize therapeutic timing. In neurodegenerative diseases, they may bypass the blood-brain barrier using targeted nanocarriers that release neuroprotective agents in response to real-time neural activity. These capabilities illustrate how smart therapeutics, powered by nanoelectronic engineering, can shift the paradigm from reactive, population-based care to predictive, proactive, and patient-specific interventions (Hu et al., 2018).

Despite their transformative potential, the clinical translation of NEDDS is significantly constrained by several challenges (Kamaly et al., 2012). Foremost among these is the lack of a coherent and adaptive regulatory environment tailored to hybrid bioelectronic systems. Current regulatory frameworks, largely designed for either traditional pharmaceuticals or standalone medical devices, are inadequately equipped to evaluate the safety, efficacy, and long-term performance of integrated nano-bioelectronic platforms. This regulatory misalignment hinders not only the approval process but also the standardization and large-scale manufacturing of NEDDS. Furthermore, ensuring sustained biocompatibility of nanoelectronic components within complex physiological environments and accounting for patient-specific biological variability add layers of complexity to clinical validation and deployment (Harun-Ur-Rashid et al., 2023; Ostroff et al., 2022). Nevertheless, sustained interdisciplinary collaboration and translational research are gradually addressing these barriers. The development of new regulatory guidelines that reflect the convergence of materials science, electronics, and biomedicine is especially critical. Such progress will be essential in establishing clear safety benchmarks, performance metrics, and ethical standards for NEDDS, ultimately facilitating their integration into routine clinical practice.

This review critically examines the conceptual underpinnings, technological architectures, clinical applications, and future directions of NEDDS within the broader context of personalized medicine. By fusing precision nanoengineering with intelligent therapeutic delivery, NEDDS not only represents a frontier in drug delivery innovation but also signals a paradigm shift in 21st-century disease management. Through an in-depth exploration of nanoscale materials, embedded electronics, and real-time physiological feedback mechanisms, this study aims to elucidate the transformative potential of NEDDS in advancing therapeutic specificity, operational efficiency, and dynamic adaptability, cornerstones of next-generation healthcare systems.

2 Methodology

2.1 Research design

This study adopts a systematic review approach aimed at exploring the historical evolution, technological development, current applications, and prospects of NEDDS. By synthesizing evidence from a wide range of peer-reviewed journal articles, clinical studies, and patent documents, this methodology offers a comprehensive and critical overview of advancements in NEDDS within the broader context of personalized medicine and nanomedicine.

2.2 Study evaluation and categorization using PRISMA framework

The review process was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework to ensure methodological transparency, consistency, and rigor. The framework was applied across four structured phases:

2.2.1 Identification

A comprehensive search was conducted across major databases: PubMed, Scopus, IEEE Xplore, Web of Science, ResearchGate, and Google Scholar. Search terms included “nanoelectronics drug delivery,” “nanotechnology in medicine,” “personalized medicine,” “pharmacogenomics,” “implantable drug delivery systems,” “targeted Drug delivery,” “controlled release mechanisms,” “biocompatibility and safety,” and “smart drug delivery.” This initial search yielded 209 records published within the last two decades. After the removal of 17 duplicates and 11 non-peer-reviewed documents, a total of 181 unique records were retained for preliminary evaluation.

2.2.2 Screening

Titles and abstracts of the 181 retained articles were screened for relevance to the scope of NEDDS. Studies were excluded if they (i) did not address drug delivery systems, (ii) lacked relevance to nanotechnology or nanoelectronics, or (iii) focused solely on unrelated biomedical technologies. Following this process, 154 articles were deemed appropriate for full-text review.

2.2.3 Eligibility assessment

The full texts of the 154 shortlisted studies were critically reviewed based on methodological soundness, clarity of focus on nanoelectronic systems, and relevance to personalized drug delivery. A total of 19 studies were excluded due to reasons such as weak experimental validation, poor data presentation, or outdated technological relevance.

2.2.4 Inclusion

Ultimately, 135 high-quality, peer-reviewed articles were included in the final synthesis. These studies formed the empirical and conceptual foundation for evaluating the historical milestones, functionality, technological components, safety profiles, and integration of NEDDS with personalized medicine and pharmacogenomics.

2.2.5 Grey literature search and appraisal

In addition to peer-reviewed publications and patent documents, relevant grey literature was systematically identified to ensure comprehensive coverage of emerging technologies within NEDDS. Grey literature sources included the World Intellectual Property Organization (WIPO), United States Patent and Trademark Office (USPTO) databases, institutional repositories, technical reports, clinical trial registries, and industry white papers accessed through ResearchGate, Google Scholar, and OpenGrey. A targeted search strategy using the same keywords as the main database search was employed to retrieve non-indexed but technically relevant documents. To maintain methodological rigor, all grey literature was appraised using the Authority, Accuracy, Coverage, Objectivity, Date, and Significance (AACODS) checklist. Documents meeting minimum criteria for authority, methodological transparency, and relevance were retained for synthesis, ensuring that patent-based innovations and non-peer-reviewed technical insights were critically and systematically integrated into the review.

2.3 Quality assessment tools

To ensure scientific rigor and reliability, two validated quality appraisal instruments were employed. The Critical Appraisal Skills Programme (CASP) Checklist was used to assess the clarity of aims, appropriateness of research design, and the validity of conclusions. In parallel, a customized version of the Modified Joanna Briggs Institute (JBI) Checklist was applied to evaluate aspects specific to technological research, including the reproducibility of design, robustness of data interpretation, and alignment with regulatory standards. Only studies scoring 7 or higher on a 10-point scale were retained for synthesis, guaranteeing inclusion of only methodologically sound literature.

2.4 Thematic coding and data categorization

A thematic analysis was performed using NVivo software to systematically code and categorize data from the selected studies. Four primary thematic domains were identified: (i) Historical and Conceptual Background, covering the origins and evolution of NEDDS; (ii) Technological Innovations, focusing on nanoelectronic components, biosensors, and microfabrication techniques; (iii) Clinical Integration and Personalized Therapy, addressing links between NEDDS, pharmacogenomics, and targeted therapy; and (iv) Safety, Efficacy, and Regulatory Considerations, examining biocompatibility, clinical trial outcomes, and approval frameworks. The use of NVivo ensured traceability and consistency across coded data, enhancing the reliability of the thematic synthesis. Figure 1 is the PRISMA diagram showing the systematic rigor evaluations and screening of the data used for this review.

Figure 1

Figure 1. PRIMA diagram.

3 Literature review

3.1 Principles of nanoelectronics in drug delivery systems

NEDDS represent a cutting-edge therapeutic platform that synergistically combines nanotechnology, electronic engineering, and medical science to achieve highly controlled, efficient, and site-specific drug delivery (Date et al., 2010). A core innovation of NEDDS is its capacity to deliver therapeutic agents, ranging from conventional pharmaceuticals to genetic materials, with exceptional precision to specific target sites within the body, significantly reducing systemic side effects and maximizing therapeutic efficacy (Date et al., 2010; Safari and Zarnegar, 2014). At the core of NEDDS are nanoscale components and embedded electronic systems, which work in tandem to achieve several fundamental principles, as illustrated in Figure 2. These principles include targeted delivery, controlled release, bioavailability enhancement, and real-time feedback-driven modulation of therapeutic regimens.

Figure 2

Figure 2. Principles of nanoelectronics in drug delivery systems.

Target specificity in NEDDS is typically achieved through the functionalization of drug carriers, such as nanoparticles conjugated with antibodies, peptides, or other ligands, that selectively bind to overexpressed receptors on the surface of diseased cells or tissues (Rosenblum et al., 2018; Masood, 2016). This molecular targeting strategy facilitates precise localization of the therapeutic payload, significantly reducing off-target effects and improving treatment efficacy. In addition to targeting, NEDDS offers temporal control over drug administration. These systems are capable of modulating the type, dose, and release kinetics of pharmaceutical agents. This feature is particularly beneficial for drugs with short biological half-lives or those requiring complex dosing regimens, as NEDDS can maintain sustained and consistent drug levels in vivo (Park, 2014; Kamaly et al., 2016). Moreover, NEDDS can address the longstanding challenge of poor solubility and limited bioavailability in certain drugs. Through nanoencapsulation techniques, these systems enhance drug solubility, improve chemical stability, and optimize absorption profiles, collectively contributing to greater therapeutic efficacy (Krstić et al., 2018; Zhang et al., 2018).

However, the development and deployment of NEDDS must consider the biocompatibility and safety of the materials used. Construction often relies on well-characterized biocompatible materials, such as lipids, polymers, or biodegradable metals, to ensure that degradation by-products do not elicit toxic or immunogenic responses (Cheng et al., 2011; Richardson et al., 1999). Advanced NEDDS are now incorporating traditional electronic components that enable real-time monitoring and programmable drug release. For instance, integrated nanoelectronic sensors can detect dynamic changes in physiological biomarkers (e.g., pH, glucose levels) and trigger therapeutic release accordingly (Kumar and Mohammad, 2011; Kar et al., 2022; Park et al., 2022; Hashida, 2020). These smart systems allow for remote control and fine-tuning of drug distribution and dosage, providing unprecedented responsiveness to the patient’s real-time condition. Additionally, NEDDS can be personalized to accommodate individual patient characteristics, including genetic profiles and disease-specific biomarkers. Functional elements of the nanoplatform, such as targeting ligands or sensor modules, can be custom-designed to recognize unique molecular signatures in a given patient, reinforcing the role of NEDDS in precision medicine (Ongesa et al., 2025; Abu-Thabit and Makhlouf, 2018). Finally, to fully realize the potential of NEDDS in clinical contexts, seamless integration with portable digital health platforms, such as mobile applications or wearable biosensors, is essential. Such integration enables accurate, real-time tracking of drug delivery and patient response, thereby closing the loop between diagnosis, treatment, and monitoring (Kar et al., 2022).

3.2 Evolution and advancements in drug delivery systems

Drug delivery systems have undergone a profound transformation, from rudimentary administration methods to highly sophisticated, targeted, and controlled-release platforms (Ongesa et al., 2025). In antiquity, natural substances were commonly used to treat diseases, often administered through primitive modalities such as chewing, inhalation, or decoctions (Thakur and Agrawal, 2015). Plant-based ointments and plasters also served as topical agents in early medical practices (Park et al., 2022). Traditional pharmacology, which emphasized the holistic use of entire plant materials, began transitioning in the 19th century with the advent of molecular pharmacology, when active therapeutic compounds were first isolated and purified from natural sources (Park et al., 2022). This advancement led to more standardized dosage forms, including tinctures, oral liquids, and ointments.

The 20th century introduced a major paradigm shift with the development of antibiotics, corticosteroids, and other high-potency therapeutics, alongside innovative dosage forms such as tablets, capsules, and injectables (Abu-Thabit and Makhlouf, 2018). These developments established the foundation for modern pharmaceutical delivery. In the 21st century, drug delivery entered a nanotechnological era. The emergence of nanocarrier-based systems, including liposomes, dendrimers, micelles, and polymeric nanoparticles, enabled controlled drug release, improved solubility of hydrophobic drugs, and enhanced site-specific targeting, thereby reducing systemic toxicity.

Building upon this foundation, NEDDS represents the latest evolutionary leap. NEDDS integrates nanoscale drug carriers with microelectronic and nanoelectronic components to enable programmable, sensor-guided, and feedback-controlled drug release. Unlike passive nanocarriers, NEDDS actively monitor physiological parameters such as pH, temperature, or glucose levels via embedded sensors, and subsequently regulate drug release in real time through actuators or remote-control mechanisms (Kar et al., 2022). This capacity for real-time therapeutic modulation marks a significant departure from earlier systems, transitioning drug delivery from static release profiles to dynamic, responsive, and personalized regimens. Moreover, NEDDS leverages advances in microfabrication, wireless communication, and biosensing to enable integration with wearable or implantable medical devices (Alam et al., 2024). These systems can be tailored to patient-specific molecular profiles and pharmacokinetics, embodying the principles of precision medicine and smart therapeutics. As such, NEDDS not only enhances the pharmacological effectiveness of treatments but also redefines the clinical approach to chronic disease management, oncology, and gene therapy. The historical evolution of drug delivery systems reflects an ongoing trajectory, from empirical and passive methods to intelligent, interactive, and personalized nanoelectronic platforms. NEDDS represent the frontier of this evolution, promising unprecedented control, specificity, and adaptability in therapeutic interventions.

3.3 Importance of precision medicine in healthcare

Precision medicine, also referred to as personalized medicine, has emerged as a groundbreaking paradigm in modern healthcare, designed to tailor disease prevention, diagnosis, and treatment strategies to individual patients based on their unique genetic, environmental, and lifestyle characteristics (Park et al., 2022). This approach stands in contrast to the traditional “one-size-fits-all” model, optimizing clinical outcomes by integrating patient-specific biological and contextual data (Stenzinger et al., 2023; Dzau and Ginsburg, 2016). The major benefits and importance of precision medicine in healthcare are outlined below:

1. Enhanced Early Diagnosis and Disease Prevention: Precision medicine improves early disease detection through advanced molecular diagnostics and predictive analytics. Unlike conventional symptom-based diagnostics, it enables the identification of subclinical and pre-symptomatic conditions by analyzing genetic risk factors and biomarkers (Dzau and Ginsburg, 2016; Ginsburg and Kathryn, 2018). This proactive approach facilitates early intervention, reduces disease progression, and minimizes long-term healthcare burdens (Farrokhi et al., 2023).

2. Personalized and Targeted Therapies: By leveraging genomic profiling and phenotypic data, precision medicine allows clinicians to select the most effective therapeutic regimens for individual patients. This personalization enhances treatment efficacy, especially for genetically complex diseases such as cancer, cardiovascular disorders, and autoimmune conditions (Stenzinger et al., 2023; Farrokhi et al., 2023). It also minimizes therapeutic resistance and increases response rates.

3. Reduction of Adverse Drug Reactions: Adverse drug reactions (ADRs) are a significant challenge in conventional medicine. Precision medicine addresses this by using pharmacogenomics to align drug selection and dosage with the patient’s genetic profile. This reduces hypersensitivity reactions, toxicity, and therapeutic failure, promoting safer and more predictable treatment outcomes (Ginsburg and Kathryn, 2018; Farrokhi et al., 2023).

4. Advancement in Oncology Treatment: Precision oncology has revolutionized cancer care by enabling the development of targeted therapies that address tumor-specific molecular abnormalities. These treatments have improved patient survival and quality of life while reducing the harmful side effects of traditional chemotherapy (Suri et al., 2007). Biomarker-driven stratification also enhances clinical trial efficiency and drug development (Suri et al., 2007).

5. Improved Clinical and Economic Outcomes: Precision medicine supports value-based healthcare by reducing trial-and-error prescribing, avoiding ineffective interventions, and minimizing hospital readmissions. This contributes to substantial cost savings for healthcare systems while simultaneously improving patient satisfaction and treatment success rates (Stenzinger et al., 2023).

6. Promotion of Patient-Centered Care: By considering patients’ genetic makeup alongside their personal values, preferences, and lifestyle factors, precision medicine fosters a more engaged and collaborative doctor-patient relationship. This alignment enhances treatment adherence, satisfaction, and health-related quality of life (Farrokhi et al., 2023; Suri et al., 2007).

7. Facilitation of Preventive and Predictive Healthcare Models: Beyond treatment, precision medicine enables long-term health planning by identifying individuals at high risk for developing certain diseases. This facilitates the implementation of lifestyle modifications, vaccination strategies, and other preventive measures tailored to personal risk profiles (Dzau and Ginsburg, 2016; Ginsburg and Kathryn, 2018).

8. Acceleration of Biomedical Research and Innovation: The precision medicine framework has catalyzed innovation in biomedical research by enabling the discovery of novel biomarkers, drug targets, and genetic pathways. It also supports the development of adaptive clinical trials and real-world data integration, accelerating the translation of research into clinical practice (Suri et al., 2007).

9. Ethical, Legal, and Social Considerations (ELSI): Despite its transformative potential, precision medicine poses ethical and practical challenges. Key concerns include data privacy, informed consent, equitable access to genomic technologies, and potential discrimination based on genetic information. Addressing these issues requires the implementation of transparent governance, strong regulatory frameworks, and inclusive healthcare policies (Stenzinger et al., 2023; Farrokhi et al., 2023).

Precision medicine marks a paradigm shift in healthcare delivery, transforming the way diseases are predicted, prevented, diagnosed, and treated. With the continuous advancement of genomic technologies, machine learning, and systems biology, precision medicine is poised to become the foundation of personalized healthcare globally (Collins and Varmus, 2015; Vignali et al., 2022; Turnbull et al., 2018; Causio et al., 2024). The conceptual framework illustrating its multidimensional importance is presented in Figure 3.

Figure 3

Figure 3. Importance of precision medicine in healthcare.

3.4 Nanotechnology in drug delivery

Nanotechnology has ushered in a paradigm shift in drug delivery by offering precise, targeted, and controlled therapeutic strategies that overcome the limitations of conventional pharmaceutical systems. The unique physicochemical properties of nanomaterials, such as a high surface-area-to-volume ratio, modifiable surface energy, and tunable surface chemistry, have enabled the development of sophisticated drug delivery platforms capable of optimizing therapeutic efficacy while minimizing adverse effects (Slamon et al., 2001; Ts et al., 2009; Lee et al., 2022; Farrokhi et al., 2023). The major nanoscale carriers include nanoparticles, liposomes, micelles, and dendrimers. These nanostructures are designed to encapsulate, protect, and transport drugs to specific biological targets, improving pharmacokinetics and pharmacodynamics (Beam and Kohane, 2018). Among them, nanoparticles are the most versatile. They can safeguard drugs from premature degradation, enhance cellular uptake, and exploit mechanisms such as the enhanced permeability and retention (EPR) effect to accumulate preferentially in diseased tissues (Suri et al., 2007; Frangoul et al., 2021).

Liposomes, composed of phospholipid bilayers, can encapsulate both hydrophilic and hydrophobic drugs. Their surfaces can be functionalized, for example, via PEGylation or ligand attachment, to increase circulation time and enable targeted delivery (Farokhzad and Langer, 2009; Emeje et al., 2012). Micelles, formed from amphiphilic block copolymers, are well-suited for solubilizing poorly water-soluble drugs. Surface modifications enhance their targeting specificity and reduce systemic toxicity (Suri et al., 2007; Farokhzad and Langer, 2009). Dendrimers, with their highly branched, monodisperse structures, offer exceptional control over size, surface functionality, and drug loading. They can encapsulate drugs within their internal cavities or conjugate them to surface functional groups, and can be tailored with targeting ligands, imaging agents, or other functional moieties (Ginsburg and Kathryn, 2018; Kar et al., 2022). These advanced nanocarriers collectively enhance the solubility, stability, and bioavailability of therapeutic agents, thereby increasing the precision and effectiveness of treatment. Nanotechnology also allows for the co-delivery of multiple drugs in a single carrier, enabling synchronized release and synergistic therapeutic effects, particularly valuable in complex or multidrug-resistant diseases (McNeil, 2011; Farokhzad and Langer, 2009; Jiang et al., 2007).

Furthermore, the controlled and sustained release capabilities of nanocarriers reduce the need for frequent dosing, ensure more consistent plasma drug levels, and minimize side effects. This results in improved patient adherence and overall treatment outcomes (Farokhzad and Langer, 2009; Jiang et al., 2007). Nanocarriers can also be engineered to avoid non-target tissues, thereby significantly lowering systemic toxicity and improving the therapeutic index (McNeil, 2011). In addition to drug delivery, many of these nanoplatforms have potential in diagnostic imaging and theranostics, further expanding their clinical utility. The integration of nanotechnology into drug delivery systems is not only revolutionizing therapeutic strategies but also paving the way for personalized medicine, where treatments can be customized to the molecular profile of individual patients (Jiang et al., 2007). Table 1 describes the advantages of personalized medicine in NEDDS.

Table 1

Table 1. Advantages of personalized medicine enabled by nanoelectronic drug delivery systems.

3.5 Integration of electronics and nanoelectronics in smart drug delivery systems

The synergistic integration of electronics and pharmacology has catalyzed a paradigm shift in drug delivery technologies, enabling controlled dosing, real-time physiological monitoring, adaptive therapeutic modulation, and remote clinical management. Smart drug delivery systems (SDDSs) and their nanoelectronic counterparts, NEDDS, are engineered platforms that leverage multi-functional electronic architectures to achieve precision medicine objectives as illustrated in Figure 4. These systems incorporate micro- to nanoscale components such as biosensors, actuators, embedded controllers, wireless communication modules, power management units, and human–machine interfaces (HMIs) into wearable, implantable, or ingestible formats, enhancing therapeutic efficacy, biocompatibility, and patient compliance (Prabhakar and Banerjee, 2020; Raijada et al., 2021; Razzacki et al., 2004) as shown in Figure 5.

Figure 4

Figure 4. Integration of electronics in drug delivery systems.

Figure 5

Figure 5. Electronic components and how they are used in the smart drugs and healthcare.

3.5.1 Evolution from microelectronic to nanoelectronic integration

Initial iterations of SDDSs utilized microscale electronics, such as biosensors, microprocessors, and microelectromechanical actuators, to facilitate closed-loop drug administration based on real-time physiological data. The transition to nanoelectronics has introduced functionalities at the cellular and subcellular scales (Mirvakili and Langer, 2021). NEDDS harness the precision of nanoscale engineering to achieve enhanced molecular sensitivity, spatiotemporally targeted delivery, and superior tissue-electronic interfacing. Nanoelectronic platforms utilize materials such as semiconductor nanowires, graphene derivatives, and molecular transistors to interact with biological environments at unprecedented resolution (Manikkath and Subramony, 2021; Dennyson Savariraj et al., 2021).

3.5.2 Advanced sensing and feedback mechanisms

The operational core of both SDDSs and NEDDS involves real-time biosensing modules that continuously monitor physiological variables such as blood glucose, pH, interstitial temperature, oxygen saturation, and disease-specific biomarkers. Traditional biosensors rely on enzymatic, electrochemical, or optical transduction mechanisms. In contrast, nanosensors, utilizing platforms such as carbon nanotubes (CNTs), quantum dots, and field-effect transistor (FET)-based devices, offer femtomolar sensitivity and single-molecule detection capabilities. These nanosensors are often integrated into wearable epidermal electronics or implantable microfluidic systems, enabling feedback-controlled, on-demand drug release in response to dynamic biological cues (Mirvakili and Langer, 2021; Manikkath and Subramony, 2021; Dennyson Savariraj et al., 2021; Eze et al., 2023a). Such sensor-driven systems support real-time decision-making, preemptive therapeutic intervention, and predictive diagnostics (Dennyson Savariraj et al., 2021).

3.5.3 Actuation and controlled drug release mechanisms

Actuation mechanisms are integral to modulating drug release kinetics and localization. In conventional SDDSs, actuation is achieved through microvalves, solenoids, electromechanical micropumps, or microneedles that are triggered by biosensor input. NEDDS utilize stimuli-responsive nanoactuators based on electrothermal, piezoelectric, photothermal, or magnetoelectric principles. These nanoactuators enable the reversible deformation of nanomembranes, rupture of nanocapsules, or opening of nanopores with sub-micrometer precision. Such precision is essential for localized delivery to pathological sites (e.g., neoplasms, neurodegenerative loci), minimizing systemic exposure and adverse effects while maximizing therapeutic payload delivery (Eze et al., 2023a; Enerst et al., 2023a).

3.5.4 Embedded computation and control algorithms

The control infrastructure in smart delivery systems comprises microcontrollers, nanoprocessors, and embedded AI modules. These processors execute real-time data acquisition, signal processing, and decision-making algorithms to modulate drug administration parameters. While SDDSs typically employ low-power microcontrollers optimized for wearable or portable devices, NEDDS incorporate nanoscale processors with ultra-low power consumption for long-term implantation (Enerst et al., 2023b; Eze et al., 2023b). The integration of machine learning (ML) and adaptive control algorithms enables pattern recognition in patient-specific responses, self-calibration of dosage schedules, and the implementation of closed-loop autonomous therapy (Eze et al., 2023c; Eze et al., 2023d). These computational advancements enhance the intelligence and personalization of drug delivery regimens.

3.5.5 Power supply and nano-energy harvesting

Reliable and sustainable energy is critical for the uninterrupted operation of SDDSs and NEDDS. Conventional systems use miniaturized rechargeable lithium-polymer or solid-state microbatteries. In contrast, nanoelectronic systems increasingly utilize energy-harvesting modalities, including nanoscale photovoltaic cells, piezoelectric nanogenerators, and thermoelectric harvesters, which convert ambient biomechanical, thermal, or light energy into electrical power (Eze et al., 2023b; Eze et al., 2022). Advanced energy storage architectures such as micro-supercapacitors and biofuel cells further support the operational autonomy of implantable devices. Integrated power management circuits ensure energy efficiency, thermal regulation, and biosafety across prolonged therapeutic windows.

3.5.6 Wireless communication and data interoperability

Wireless telemetry is vital for interfacing drug delivery devices with external monitoring platforms and healthcare databases. Communication modules, including Bluetooth Low Energy (BLE), Wi-Fi, Near Field Communication (NFC), and nanoantennae, facilitate secure data transmission to clinicians and caregivers (Eze et al., 2023d; Eze et al., 2022; Eze et al., 2017; Eze, 2023). Such connectivity enables remote patient monitoring, dynamic therapy adjustment, and integration with electronic health records (EHRs). Interoperability with hospital information systems (HIS) and clinical decision support systems (CDSS) enhances diagnostic accuracy, ensures compliance with treatment protocols, and streamlines data-driven medical interventions.

3.5.7 Human–machine interfaces and patient engagement

User-centered interface design plays a pivotal role in patient adherence and therapeutic outcomes. Interfaces include mobile applications, wearable displays, haptic feedback systems, and auditory alerts that provide real-time feedback on dosing status, device performance, and physiological trends (Eze et al., 2023e; Eze et al., 2016; Jacob et al., 2020). Features such as interactive dashboards, educational prompts, and manual override controls enhance patient engagement, self-management capabilities, and digital health literacy. These systems can be further integrated with personalized behavioral feedback algorithms to support chronic disease management and remote therapy adherence.

3.5.8 Biocompatibility, encapsulation, and safety engineering

Biocompatibility and long-term physiological stability are critical parameters in the design of SDDSs and NEDDS, particularly for implantable, ingestible, or skin-contact applications (Fathi-karkan et al., 2024; Rezaei et al., 2021). Biocompatibility begins at the material selection phase, where components such as sensors, electrodes, substrates, and interconnects must be non-toxic, non-immunogenic, and chemically stable in biological environments. Common sensor materials like platinum, gold, titanium, and conductive polymers (e.g., PEDOT:PSS) are widely used due to their electrochemical stability and minimal cytotoxicity. Flexible electronics often integrate biocompatible substrates like polyimide, PDMS (polydimethylsiloxane), and silk fibroin for conformal contact with tissues (Saghati et al., 2021).

The power sources in these systems also demand high safety standards and the incorporation of renewable energy systems (Eze et al., 2023b). For instance, solid-state microbatteries, solar energy, and biofuel cells are preferred over conventional lithium-ion batteries due to reduced risk of electrolyte leakage, thermal runaway, or chemical exposure (Eze et al., 2025; Eze et al., 2024a). For lithium-based systems, hermetically sealed packaging, battery encapsulation in biocompatible coatings, and electrochemical overcharge protection are crucial. Additionally, battery safety mechanisms include thermal sensors, fuse circuits, and charge regulators to mitigate overheating and prevent electrical faults (Eze et al., 2024b; Eze et al., 2024c). Encapsulation technologies vary depending on the system’s operational environment. SDDSs typically use polymeric encapsulations with moisture, pH, and dust resistance, employing materials such as Parylene C, PDMS, and medical-grade epoxies (Pourmadadi et al., 2024). In contrast, NEDDS leverage advanced nanocoatings, such as polyethylene glycol (PEG) for stealth behavior, silicon carbide (SiC) and graphene oxide for corrosion resistance, and zwitterionic hydrogels for anti-fouling properties. These coatings are essential to minimize biofouling, prevent degradation, and evade immune recognition, thereby prolonging device function and patient safety (Sun, 2014; Bakhshi et al., 2024).

In terms of system-level safety engineering, features include redundant circuit protection, closed-loop feedback mechanisms, leakage and rupture detection, overdose prevention alarms, thermal regulation units, and automated shutdown protocols in case of anomalies (Eze et al., 2022; Eze et al., 2017; Eze, 2023; Eze et al., 2025; Eze et al., 2024a; Eze et al., 2024b). These are especially critical in high-risk therapeutic domains such as oncology (chemotherapy infusion systems), endocrinology (automated insulin pumps), and neuroscience (deep brain stimulation and neuromodulation). All device components and materials must comply with internationally recognized biocompatibility and safety standards, including ISO 10993 (biological evaluation of medical devices), IEC 60601 (medical electrical equipment), and Food and Drug Administration (FDA) Class II or III medical device classifications, depending on the level of risk and invasiveness (Ravizza et al., 2019). Rigorous preclinical and clinical testing is mandated for approval, particularly for long-term implantables or controlled-release systems in human subjects (Jiang et al., 2024; Martín del Valle et al., 2009; Staples et al., 2006; Bar-Zeev et al., 2017).

3.5.9 Integration of lab-on-a-chip and nano-biointerfaces

One of the most transformative innovations in NEDDS is the integration of lab-on-a-chip (LoC) platforms that miniaturize laboratory functions onto single microfluidic chips. These platforms embed nanoelectromechanical systems (NEMS), nanofluidic channels, and FET-based biosensors for multiplexed, label-free detection of biomarkers in biofluids such as saliva, sweat, interstitial fluid, or cerebrospinal fluid (Eze et al., 2023b; Eze et al., 2023c). In parallel, biofunctional nano-interfaces, including self-assembled monolayers (SAMs), peptide-functionalized nanoparticles, and nanostructured substrates, enable high-affinity interactions between electronic components and biological tissues. These interfaces optimize signal transduction, minimize inflammatory response, and support long-term integration in biological environments (Enerst et al., 2023b).

The progressive integration of micro- and nanoelectronic components into smart drug delivery systems marks a profound advancement in translational medicine, enabling personalized, autonomous, and minimally invasive therapies as illustrated in Table 2. From macroscale decision systems to nanoscale bio-interactive platforms, these technologies collectively enhance the spatiotemporal precision, biosafety, and responsiveness of pharmacological interventions. Continued interdisciplinary innovation in this domain promises to redefine therapeutic delivery models, supporting the global shift toward precision health, remote care, and next-generation bioelectronic medicine.

Table 2

Table 2. Components of nanoelectronic drug delivery systems.

3.6 Targeted drug delivery for specific diseases

NEDDS represent a groundbreaking advancement in precision medicine by enabling site-specific delivery of therapeutic agents within the human body. These systems incorporate nano-sized carriers, such as liposomes, dendrimers, and polymeric or metallic nanoparticles, engineered with high specificity to identify, bind, and deliver drugs directly to diseased tissues (e.g., cancerous tumors, inflamed sites, or infected organs) (Mitchell et al., 2021; Roses, 2000). The primary goal is to maximize therapeutic efficiency at the target site while minimizing drug exposure to healthy tissues, thereby reducing adverse side effects and improving patient outcomes.

3.6.1 Active targeting

Active targeting involves the functionalization of nanoparticles with specific biological ligands that can recognize and bind selectively to molecular markers overexpressed on diseased cells. This strategy typically employs ligands such as monoclonal antibodies, peptides, aptamers, or small molecules that have a high affinity for target receptors, such as folate receptors in ovarian cancer or HER2 receptors, together with AI in certain breast cancers (Tabar et al., 2024; Alavinejad et al., 2025). Once administered, these engineered nanoparticles circulate through the bloodstream and bind specifically to cells expressing the corresponding receptors, initiating receptor-mediated endocytosis for cellular uptake. This targeted delivery enhances drug accumulation at the pathological site, improves therapeutic efficacy, and minimizes systemic toxicity to healthy tissues (Ahmed et al., 2016; Wang et al., 2013). A well-known example is the use of anti-HER2 antibody-conjugated nanoparticles in HER2-positive breast cancer, which allows for selective targeting of tumor cells while sparing normal tissue, thereby facilitating personalized cancer treatment.

3.6.2 Passive targeting

Passive targeting leverages the inherent physiological characteristics of diseased tissues, particularly the EPR effect, to direct nanoparticles to pathological sites without the need for specific targeting ligands. In solid tumors, rapid and defective angiogenesis leads to the formation of abnormal, highly permeable blood vessels with large fenestrations (ranging from 100 to 800 nm), which facilitate the extravasation and accumulation of nanoparticles (Ahmed et al., 2016). Furthermore, tumors typically exhibit inefficient lymphatic drainage, allowing nanoparticles to remain in the tumor microenvironment for prolonged periods, thereby enhancing local drug concentration. Nanoparticles within the size range of 10–200 nm are especially suited to exploit the EPR effect for tumor accumulation. This passive delivery approach is exemplified by Doxil®, a PEGylated liposomal formulation of doxorubicin, which accumulates in tumors through the EPR effect and significantly reduces the cardiotoxicity commonly associated with conventional doxorubicin therapy (Wang et al., 2013).

3.7 Advanced drug release strategies and combination therapies in NEDDS

NEDDS represent a significant leap in the development of precision-targeted pharmacotherapy. These platforms are uniquely positioned to address the limitations of conventional drug administration, particularly in the treatment of complex and heterogeneous diseases such as cancer, neurodegenerative disorders, and chronic inflammatory conditions. By integrating nanoscale electronics with responsive biomaterials, NEDDS enable programmable, site-specific, and temporally controlled drug delivery, thus optimizing pharmacokinetic profiles, minimizing systemic toxicity, and enhancing patient adherence, especially for therapeutics with narrow therapeutic indices or demanding dosing schedules (Roses, 2000; Ahmed et al., 2016).

3.7.1 Controlled and stimuli-responsive release mechanisms

A fundamental advantage of NEDDS is their capacity to achieve controlled and stimuli-responsive drug release, allowing precise modulation of therapeutic delivery in response to specific biological or externally applied cues. These systems are designed using intelligent nanomaterials, such as pH-sensitive polymers, thermoresponsive hydrogels, and nanoparticles sensitive to light, magnetic fields, or ultrasound, which undergo physicochemical changes that regulate drug release kinetics with exceptional spatial and temporal accuracy.

3.7.1.1 Internal stimuli-responsive systems

Endogenous stimuli-responsive NEDDS leverage the unique microenvironment of pathological tissues to achieve site-specific and autonomous drug delivery. For example, pH-responsive nanocarriers are engineered to exploit the acidic conditions commonly found in tumor microenvironments and inflamed tissues. When exposed to such environments, the acidic pH triggers protonation or conformational changes in the polymeric matrix, facilitating the targeted release of encapsulated drugs (Balogun et al., 2024; Fathi-karkan et al., 2024).

Similarly, thermoresponsive systems respond to localized temperature elevations, often observed in malignant tissues due to heightened metabolic activity, by undergoing phase transitions (e.g., sol-gel transformation) that release their payload. Additional internal triggers include: Redox gradients, particularly elevated glutathione levels in cancer cells, Overexpressed enzymes such as matrix metalloproteinases (MMPs), and Reactive oxygen species (ROS) are prevalent in oxidative stress conditions. These internal mechanisms offer passive yet highly selective release profiles, reducing systemic toxicity while enhancing the therapeutic index (Karkan et al., 2022; Rezaei et al., 2021).

3.7.1.2 External stimuli-responsive systems

Externally triggered NEDDS are engineered to respond to non-invasive, controllable stimuli, allowing clinicians to fine-tune drug release in real-time and adapt treatment protocols dynamically. Notable systems include:

➢ Photoresponsive nanocarriers, which utilize specific light wavelengths (e.g., near-infrared) to penetrate tissues and trigger bond cleavage or thermal effects, leading to localized drug discharge with minimal damage to adjacent healthy tissue (Mitchell et al., 2021; Roses, 2000).

➢ Magnetically responsive nanoparticles, which can be guided to target sites using static magnetic fields and activated by alternating magnetic fields to induce localized hyperthermia or disrupt carrier structure.

➢ Ultrasound-responsive systems, such as sonosensitive liposomes and micelles, which harness acoustic cavitation to increase membrane permeability or cause carrier rupture, enabling spatially targeted release (Zhang et al., 2020; Bakhshi et al., 2024).

These platforms offer on-demand, externally controllable release, making them ideal for precision medicine applications. They facilitate therapeutic flexibility, reduce the need for repeated dosing, and support real-time customization of treatment regimens.

3.7.2 Integration of combination therapy in NEDDS

The architectural versatility of NEDDS supports the design of multimodal therapeutic platforms, enabling the co-delivery of multiple drugs or therapeutic agents within a single nanosystem. This capability is particularly valuable in the management of multifactorial and treatment-resistant diseases, such as cancer, HIV/AIDS, and neurodegenerative disorders, where monotherapy is often insufficient. By enabling combination therapy, NEDDS improve therapeutic efficacy, reduce resistance, and exploit synergistic pharmacodynamic interactions (Roses, 2000; Ahmed et al., 2016).

3.7.2.1 Sequential drug release

Sequential release strategies involve the time-staggered delivery of therapeutic agents from a single nanocarrier, allowing for precise control over the order and timing of drug actions. These systems are typically designed using multilayered nanoparticles, core-shell architectures, or stimuli-responsive compartments that degrade or activate at different rates or in response to distinct cues. For example, in oncology, a nanocarrier may first release a conventional chemotherapeutic agent (e.g., doxorubicin) to shrink the primary tumor bulk. Subsequently, a targeted molecular agent (e.g., tyrosine kinase inhibitor or anti-VEGF molecule) is released to eliminate residual chemoresistant subpopulations or to reprogram the tumor microenvironment (Ahmed et al., 2016; Karkan et al., 2022). This temporally modulated approach enhances therapeutic selectivity and minimizes systemic toxicity by coordinating pharmacological interventions to align with disease progression and tissue-specific response. Sequential release is also advantageous in multi-stage infections, such as tuberculosis or HIV, where initial microbial suppression must be followed by immune modulation or latency reversal to achieve long-term remission.

3.7.2.2 Simultaneous drug release

In contrast, simultaneous co-delivery refers to the synchronous release of multiple drugs with complementary or synergistic modes of action. This strategy is particularly effective in rapidly progressing diseases where concurrent molecular disruption of multiple pathways is necessary for therapeutic success. For instance, co-encapsulation of a DNA intercalator (e.g., cisplatin) with a cell cycle checkpoint inhibitor (e.g., CHK1/ATR inhibitor) enables a dual assault on proliferating cancer cells, inducing robust cytotoxic synergy and potentially bypassing resistance mechanisms (Wang et al., 2013; Balogun et al., 2024; Karkan et al., 2022; Zhang et al., 2020). Simultaneous release systems also facilitate dose reduction, minimizing adverse effects while preserving or even enhancing efficacy, an especially critical advantage in pediatric or elderly populations. Moreover, these platforms can incorporate a wide range of therapeutic combinations, including: Immunomodulators (e.g., checkpoint inhibitors, cytokines), Anti-angiogenic agents (e.g., bevacizumab), Gene-editing or gene-silencing constructs (e.g., siRNA, CRISPR-Cas9 systems), and Antimicrobials and adjuvants for tackling persistent infections. Such systems-level therapeutic integration enables a holistic intervention approach that addresses both primary pathology and secondary resistance or relapse mechanisms (Pourmadadi et al., 2024).

3.8 Integration of NEDDS with other therapeutic modalities

NEDDS exhibit immense potential when integrated with advanced therapeutic modalities such as immunotherapy and gene therapy. These systems provide a versatile platform to overcome conventional drug delivery challenges, including poor bioavailability, systemic toxicity, and non-specific targeting. In cancer immunotherapy, lipid-based NEDDS have been effectively employed for the co-delivery of immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 antibodies) and tumor-associated antigens. For instance (Cheng et al., 2020), utilized lipid nanoparticles to encapsulate both CpG oligonucleotides (immune adjuvants) and tumor antigens, facilitating targeted delivery to dendritic cells in lymph nodes. This approach significantly enhanced antigen presentation and T-cell activation, leading to pronounced tumor regression in melanoma models. Similarly, polymer-based NEDDS have shown promise in reprogramming tumor-associated macrophages (TAMs) from an immunosuppressive M2 phenotype to a pro-inflammatory M1 state. The scholar in (Sartawi et al., 2020) developed PLGA-PEG nanoparticles co-loaded with a CSF-1R inhibitor and interleukin-12 (IL-12), specifically targeting TAMs and modulating the tumor microenvironment to boost the efficacy of checkpoint blockade therapies.

In gene therapy, NEDDS have emerged as precise and protective carriers for nucleic acid-based interventions. For example, gold nanoparticles (AuNPs) functionalized with cationic polymers have been employed to deliver CRISPR/Cas9 ribonucleoprotein (RNP) complexes for gene editing in Duchenne Muscular Dystrophy (DMD). This enabled efficient exon skipping and restoration of dystrophin expression, as demonstrated by Lee et al. (2017). Moreover, lipid nanoparticle (LNP)-based NEDDS have revolutionized mRNA-based genetic vaccines, as exemplified by the Pfizer-BioNTech and Moderna COVID-19 vaccines. These platforms encapsulate mRNA encoding the SARS-CoV-2 spike protein, protecting it from enzymatic degradation and enabling intracellular translation to elicit robust adaptive immune responses (Karkan et al., 2022).

Beyond individual modalities, NEDDS facilitates the co-delivery of agents in synergistic immuno-gene therapy strategies. A notable example is the development of a cationic liposome system modified with a tumor-targeting peptide to simultaneously deliver IL-15 plasmid DNA and STAT3-targeting siRNA in colorectal cancer treatment. This multifunctional nanoplatform, reported by Li et al. (2019), induced potent immune stimulation while silencing oncogenic signaling pathways, resulting in marked tumor growth inhibition.

Overall, the integration of NEDDS with immunotherapeutic and gene therapy strategies offers significant advantages, including enhanced site-specific delivery, improved therapeutic efficacy, reduced off-target effects, and the ability to overcome biological barriers such as immune evasion and endosomal entrapment. This integrative approach represents a promising direction in the advancement of personalized medicine, particularly in the treatment of oncology, genetic disorders, and immune-mediated diseases.

3.9 Precision medicine and nanotechnology-driven drug delivery

Precision medicine, also known as personalized medicine, aims to tailor therapeutic strategies to the unique characteristics of individual patients, such as genetic makeup, environmental exposures, and lifestyle factors (Ahmed et al., 2016; Wang et al., 2013). NEDDS are well aligned with this approach, offering unparalleled precision in controlling drug dosage, release kinetics, and targeted delivery to specific tissues or cell types (Bar-Zeev et al., 2017; Mitchell et al., 2021). Their programmable nature enables the fine-tuning of therapeutic regimens to accommodate patient-specific physiological or pathological cues.

3.9.1 Personalized pharmaceutical delivery

NEDDS supports various drug release strategies, including periodic, sequential, and event-triggered delivery. For example, an implantable nanoelectronic device placed near a tumor site can be programmed to release chemotherapeutic agents upon detecting tumor-specific biomarkers (Martín del Valle et al., 2009; Ahmed et al., 2016; Wang et al., 2013). This level of responsiveness enables real-time, localized therapy that reduces systemic exposure and improves patient outcomes.

3.9.2 Role of pharmacogenomics in personalized therapy

Pharmacogenomics, the study of how genetic differences influence drug response, plays a pivotal role in optimizing treatment efficacy and safety. NEDDS can incorporate pharmacogenomic data to dynamically adjust drug delivery parameters such as dosage, release rate, or timing based on the patient’s genetic profile (Mitchell et al., 2021; Roses, 2000). For instance, individuals harboring genetic polymorphisms that affect drug metabolism can benefit from NEDDS programmed to modify the pharmacokinetics of therapeutic agents accordingly, thereby reducing the risk of adverse drug reactions while maintaining therapeutic efficacy (Ahmed et al., 2016; Wang et al., 2013).

3.10 Role of pharmacogenomics in personalized drug treatment

Pharmacogenomics is the field of study that focuses on the genes involved in drug reacting. This is made for the expression of genetic variations that affect drug effectiveness or safety (Mitchell et al., 2021; Roses, 2000). NEDDS are engineered to take advantage of the information from the results of pharmacogenomics tests by delivering drugs that aim for optimal therapeutic effects with minimal adverse reactions (Ahmed et al., 2016). For example, if a patient has a polymorphism that influences drug metabolism, the NEDDS can adjust the drug dose or release rate according to that (Wang et al., 2013). Advantages of Personalized Medicine through NEDDS are illustrated in Figure 6.

Figure 6

Figure 6. Schematic diagram showing the advantages of personalized medicine through NEDDS.

3.10.1 Advantages of nanoelectronic drug delivery systems in precision medicine

NEDDS provides numerous advantages that are revolutionizing the field of precision medicine. One of the most significant benefits is enhanced therapeutic efficacy, as NEDDS enable increased drug concentrations precisely at the desired site of action, thereby improving treatment outcomes (Wang et al., 2013). By targeting diseased tissues selectively, these systems also contribute to reduced side effects, minimizing drug exposure to healthy tissues and decreasing the incidence of adverse reactions (Wang et al., 2013). Another critical advantage is improved patient compliance, as the drug release profiles can be meticulously programmed to match individual therapeutic needs and schedules. Furthermore, some NEDDS are equipped with integrated sensors capable of monitoring physiological parameters or disease-specific biomarkers, allowing for real-time health monitoring. This feedback provides clinicians with timely data to make informed treatment decisions and administer interventions accordingly (Balogun et al., 2024).

NEDDS also facilitate the co-administration of multiple drugs, either simultaneously or sequentially, enabling combination therapies that leverage synergistic effects to target complex disease pathways more effectively (Balogun et al., 2024). Their design can support early disease detection by identifying biomarkers at preclinical stages, thereby enabling prompt therapeutic intervention. Importantly, by delivering drugs directly to the pathological site, NEDDS reduce systemic drug exposure and help mitigate drug resistance, a major limitation in conventional treatments (Eze et al., 2022). These systems thus contribute to an improved quality of life for patients by enhancing therapeutic precision and reducing treatment burdens (Balogun et al., 2024). Although the initial development of NEDDS may incur higher costs, its ability to reduce hospital stays, minimize drug wastage, and eliminate the need for additional treatments due to complications leads to long-term cost savings (Ahmed et al., 2016). Additionally, precision medicine strategies involving NEDDS offer the potential for patient empowerment, allowing individuals to better understand and actively participate in their therapy by aligning treatment with their unique genetic and physiological characteristics (Ahmed et al., 2016). Ultimately, NEDDS lie at the forefront of transformative drug delivery technologies. By leveraging personalized, pharmacogenomically-informed strategies, these systems offer a future of medicine characterized by enhanced treatment effectiveness, minimized side effects, and accelerated recovery, thereby ushering in a new era of patient-centered healthcare (Balogun et al., 2024).

3.11 Compatibility of nanomaterials with biological systems

The compatibility of nanomaterials with biological systems remains one of the most critical challenges in the development and clinical translation of nanoelectronic drug delivery systems (NEDDS). Biocompatibility is governed not only by the intrinsic properties of the nanomaterial but also by its degradation behavior, surface chemistry, and dynamic interactions with biological environments. In particular, the degradation of nanomaterials into potentially hazardous by-products necessitates rigorous scrutiny, as these processes can directly influence cytotoxicity, immunogenicity, and long-term tissue responses.

Several studies have demonstrated that iron oxide nanoparticles may undergo partial dissolution under physiological conditions, releasing cytotoxic Fe²⁺ and Fe³⁺ ions that can disrupt cellular homeostasis and induce oxidative stress (Zhang et al., 2020; Ghezzi et al., 2021). More broadly, metallic and semiconductor nanoparticles are known to catalyze the formation of reactive oxygen species (ROS), leading to oxidative damage to cellular membranes, proteins, and nucleic acids (Silverå Ejneby et al., 2022; Bilal et al., 2020). For example, titanium dioxide nanoparticles exhibit photo-reactive behavior, generating toxic ROS via electron transfer reactions under ultraviolet (UV) irradiation, which has been shown to significantly reduce cell viability under such exposure conditions (Chaudhary et al., 2019). These findings highlight the importance of linking degradation pathways and released chemical species to specific toxicological outcomes when evaluating nanomaterial safety.

Surface engineering plays a central role in modulating these biological interactions. Nanoparticle surface coatings are frequently employed to enhance dispersion in aqueous or organic media, improve in vivo targeting, and mitigate adverse biological responses (Gebel et al., 2014). The functionality and toxicity profile of a nanomaterial are therefore highly dependent on the composition, stability, and biological persistence of these surface modifications (Rezaei et al., 2021). In lipid-based nanocarriers, such as liposomes and nanoemulsions, biocompatibility is generally favorable due to their structural similarity to cellular membranes and their metabolism into endogenous lipid components (Farokhzad and Langer, 2009; Emeje et al., 2012). However, unmodified lipid systems are prone to rapid opsonization and clearance by the mononuclear phagocyte system. Surface modification strategies such as PEGylation have been shown to reduce protein adsorption, complement activation, and immunogenic recognition, thereby prolonging circulation time and improving in vivo tolerance (Farokhzad and Langer, 2009; Sun, 2014), although repeated administration has been associated with the emergence of anti-PEG immune responses in some cases (Bakhshi et al., 2024).

Polymer-based nanocarriers, including PLGA nanoparticles and PEG–PLA micelles, offer tunable degradation kinetics and mechanical stability, making them attractive for controlled drug release applications. Nevertheless, their biocompatibility is strongly influenced by polymer chemistry, molecular weight, and degradation by-products. Polymeric micelles, characterized by a hydrophobic core and hydrophilic shell, exhibit stability that is inversely related to their exchangeability with the surrounding biological milieu (Gebel et al., 2014). Low-stability micelles may rapidly exchange encapsulated drugs with serum proteins following injection, leading to prolonged circulation of degradation products and preferential accumulation in the liver and spleen (Lai et al., 2018). While such behavior can be exploited for passive targeting, it may hinder effective solid tumor therapy and induce toxicity within the reticuloendothelial system.

Importantly, nanomaterial biocompatibility is also governed by dose-dependent exposure and in vivo degradation kinetics. Increasing nanocarrier concentrations can saturate clearance pathways within the reticuloendothelial system, resulting in enhanced off-target accumulation in the liver and spleen, prolonged residence times, and elevated inflammatory burden (Lai et al., 2018; Pund et al., 2014). For biodegradable lipid- and polymer-based NEDDS, degradation rates and metabolic by-products are highly formulation-dependent; slow hydrolysis or incomplete degradation may lead to extended systemic persistence and accumulation of acidic or redox-active intermediates (Rezaei et al., 2021; Gebel et al., 2014). In contrast, metallic and carbon-based nanomaterials often exhibit limited biodegradation, raising concerns regarding cumulative dose effects and chronic tissue retention following repeated or long-term administration (Zhang et al., 2020; Silverå Ejneby et al., 2022).

Metallic and carbon-based nanomaterials introduce additional long-term safety considerations due to their persistence, ion release, and surface-driven redox activity. Carbon-based nanomaterials, such as carbon nanotubes and graphene oxide, are of particular interest for nanoelectronic interfacing because of their exceptional electrical conductivity and large surface area. However, their biocompatibility is highly dependent on surface functionalization. Pristine graphene derivatives have been associated with membrane disruption, ROS generation, inflammatory signaling, and chronic tissue accumulation, whereas PEGylated or carboxylated graphene oxide exhibits significantly reduced macrophage activation, oxidative stress, and fibrotic responses (Manikkath and Subramony, 2021; Dennyson Savariraj et al., 2021; Sun, 2014). Similarly, inhalation exposure to carbon nanotubes or their degradation products has raised concerns regarding pulmonary toxicity and inflammation, underscoring the importance of exposure route and material persistence in safety assessments (Lai et al., 2018).

Overall, biocompatibility in NEDDS should be understood as an emergent property arising from the interplay between nanomaterial composition, surface chemistry, degradation behavior, exposure duration, and biological context rather than as an inherent characteristic of a given material class (Chaudhary et al., 2019; Pund et al., 2014). These considerations emphas ize the necessit of comparative, mechanism-driven, and dose-resolved toxicity evaluations across lipid, polymeric, metallic, and carbon-based nanomaterials. Such an approach is essential for the rational design of safe, effective, and clinically translatable nanoelectronic drug delivery platforms.

Table 3 shows that Biocompatibility in NEDDS is not an intrinsic material property but an emergent outcome of composition, surface chemistry, degradation behavior, exposure duration, and biological context. Comparative, mechanism-driven evaluation across material classes is therefore essential for safe clinical translation.

Table 3

Table 3. Comparative differentiation of nanomaterial classes used in NEDDS.

3.12 Safety assessments and regulations for NEDDS

Regulations are firmly in place to evaluate the safety and efficacy of pharmaceutical and combination products, including emerging platforms such as NEDDS (Pund et al., 2014). In the United States, drug products and combination devices are primarily regulated by the FDA under frameworks such as the Federal Food, Drug, and Cosmetic Act (FDCA) and the Public Health Service Act (PHSA) (Rosenthal, 2020). NEDDS that incorporate both drug and device components, especially those that are implantable or programmable, fall under the purview of combination product regulation and must adhere to stringent guidelines for both device and pharmaceutical components.

Among the highest-risk categories are drug and biologic products that are used for the treatment of serious or life-threatening diseases, those intended for implantation, and those that may pose unreasonable risks if ineffective (De Michiel, 1982). Consequently, high-risk NEDDS, such as implantable nanoelectronic systems delivering immunotherapies or chemotherapeutics, are subject to premarket approval (PMA) processes and must demonstrate substantial evidence of safety and efficacy in accordance with the FDA’s regulatory requirements (Verma et al., 2021).

A significant regulatory advancement pertinent to NEDDS is the FDA’s 2023 Draft Guidance for Industry and FDA Staff on Implanted Sensor Systems, which establishes a structured framework for assessing the safety and performance of smart implantable devices. This guidance addresses critical factors such as material biocompatibility in line with ISO 10993, the safety and reliability of energy harvesting mechanisms and power supplies, data integrity and secure transmission, and the electromagnetic interactions between device components and biological tissues (De Jong and Borm, 2008). It also places strong emphasis on human factors engineering, ensuring device safety across the entire lifecycle. Since many NEDDS incorporate wireless communication, nanoelectromechanical systems (NEMS), or biosensors to enable real-time feedback and adaptive drug release, the guidance underscores the necessity of comprehensive end-to-end testing and clinical validation. For devices with programmable or responsive delivery profiles, developers are required to demonstrate the reliability of embedded algorithms, the safety of automated control loops, and the presence of fail-safe mechanisms to mitigate unintended risks (De Jong and Borm, 2008).

In the European Union, NEDDS are regulated under the European Medicines Agency (EMA) and the Medical Device Regulation (EU MDR 2017/745), which became fully enforceable in May 2021. When a NEDDS incorporates a substance that exerts an ancillary pharmacological effect, it is classified and regulated as a medical device incorporating a medicinal product (Singh et al., 2012). According to Annex I of the MDR, safety evaluations must encompass comprehensive risk management in compliance with ISO 14971, clinical evaluation, and post-market surveillance, and conformity assessments conducted by Notified Bodies, particularly for Class III devices, which include implantable or active drug delivery systems. The EMA’s Innovation Task Force (ITF) and the European Commission’s Scientific Committee on Health, Environmental and Emerging Risks (SCHEER) have emphasized the necessity for nano-specific safety protocols, urging developers to conduct toxicological profiling, biodegradation studies, and risk assessments tailored to nanoscale interactions. Special consideration is required for evaluating tissue accumulation, cellular-level interactions, and the potential for immunogenic responses, ensuring that NEDDS meet the stringent standards for both medical devices and medicinal products within the EU regulatory framework (Herrmann et al., 2021).

The global commercialization of smart nanoelectronic platforms, including both wearable and implantable NEDDS, has created an urgent demand for regulatory convergence to facilitate consistent safety and efficacy standards across borders. Organizations like the International Medical Device Regulators Forum (IMDRF) and the International Organization for Standardization (ISO) have played key roles in developing harmonized guidelines to address these challenges (Ghaderi et al., 2011). Among the most relevant standards are ISO 13485, which governs quality management systems for medical devices; ISO 14971:2019, focused on risk management specific to medical devices; the ISO/IEC 80001 series, which addresses IT network risk management for connected medical devices; and ISO/TR 10993-22, which provides protocols for biocompatibility testing of nanomaterials (National Institute of Standards and Technology NIST, 2020). These internationally recognized frameworks enable streamlined regulatory processes, including joint reviews and mutual recognition of conformity assessments by major regulatory authorities such as the FDA, EMA, PMDA (Japan), and Health Canada, thereby supporting the global deployment of safe and effective nanoelectronic drug delivery technologies (Ghaderi et al., 2011).

Due to their intricate nano- and microelectronic architectures, NEDDS require thorough evaluation to ensure safety and compatibility with the human body. Critical assessments must address potential cytotoxicity and genotoxicity arising from nano-scale surfaces or any released particles, as well as the effects of thermal and electromagnetic interactions between the device and surrounding tissues. Additionally, the stability and degradation behavior of these systems under physiological conditions must be characterized to prevent harmful byproducts or loss of function. Another crucial aspect is the evaluation of any unintended immune or inflammatory responses, which can compromise patient safety or device performance (Ravizza et al., 2019; Ghaderi et al., 2011). Given that many NEDDS enable precision-controlled microdosing, these systems may reduce systemic drug exposure but simultaneously introduce risks such as dose variability, device malfunctions, or incomplete drug release. As a result, human factors engineering and comprehensive use-error risk assessments have become essential components of regulatory submissions for these smart drug delivery technologies. With pharmaceutical research and development becoming increasingly globalized, there is a growing consensus among developers and regulators to adopt common international standards and guidelines for evaluating NEDDS. Harmonizing both preclinical evaluation protocols and clinical investigation frameworks is vital to address the complex interplay between electronics, biological systems, and pharmacology unique to these devices, thereby facilitating streamlined regulatory approvals across different jurisdictions (Ghaderi et al., 2011).

3.12.1 Phase II/III and real-world evidence (RWE) considerations

The translation of nanoelectronic drug delivery systems (NEDDS) from preclinical research to clinical practice requires systematic evaluation through Phase II/III trials, followed by real-world evidence (RWE) studies. Phase II trials primarily assess preliminary efficacy, optimal dosing, and safety profiles in defined patient populations, providing essential data to guide subsequent trial design. Phase III trials expand these evaluations to larger, more diverse cohorts to confirm efficacy, monitor adverse events, and generate the evidence necessary for regulatory approval. Complementing these trials, RWE studies capture long-term safety, device performance, patient adherence, and comparative effectiveness in routine clinical practice outside the controlled settings of clinical trials. RWE is particularly valuable for assessing the real-world applicability and scalability of NEDDS across diverse healthcare contexts, including resource-limited settings.

Table 4 summarizes the clinical development and real-world evaluation of nanomedicine drug delivery platforms, highlighting that these technologies are most advanced in Phase II/III trials globally. Real-world evidence (RWE), as illustrated by post-market surveillance of approved nanomedicines such as Abraxane® and lipid nanoparticle-based vaccines, provides valuable long-term data on safety and effectiveness beyond controlled trials. Notable limitations include small cohort sizes in some Phase II studies, variable efficacy outcomes, and a lack of head-to-head Phase III comparisons for many nanoplatforms. Additionally, published RWE specifically focused on nano-enabled drug delivery devices remains scarce, indicating a critical gap for future research and reporting.

Table 4

Table 4. Summary of clinical and real-world studies of NEDDS.

3.13 Mitigation strategies for potential risks in nanoelectronic drug delivery

Developing specific risk mitigation strategies for potential issues with NEDDS necessarily means starting by addressing the lack of knowledge we currently have concerning the safety and biocompatibility of nanomaterials, as well as about how to design safer systems in the future (De Jong and Borm, 2008). Addressing the existing problems to date entails the design of in vitro systems that are similar to the in vivo ones to enable exhaustive investigations of any side effects induced by the nanomaterials. The in vitro tests, along with pharmacological models, should be considered as a substitution for the traditional animal testing (Singh et al., 2012). However, these tactics could be very effective only in case of significant funding and resources that would be provided from both a side of government and a side of industry (Herrmann et al., 2021). Concerning the existing economic situation, along with this nature of the problem, it is necessary not to oversee the question of a predictive computational model development for the probability and the degree of the adverse effects a nanomaterial can have, which will help to reduce the in vivo investigations that are used to assess nanomaterial security. With a better solution for current problems, would come strategic designs that might help to counter future risks (Ghaderi et al., 2011). Therefore, safety should be the primary concern. This may comprise nanoparticles’ imprisonment in a more significant transportation system, acting to contrast the exposure of the carrier to neighboring tissues. Incorporation of the nano-materials, which degrade and get excreted out of the body once the material is released, is safer than those materials which keep on staying within the body. On the one hand, either method embodies the main principle of reshaping the existing reality, but this is a great necessity to make this treatment longer-lasting and safe (Wen et al., 2015).

3.14 Future directions and challenges of NEDD

3.14.1 Emerging trends in nanoelectronic drug delivery research

Nanotechnology has shown great promise in recent years for providing improved therapeutics and diagnostics of various diseases (Adepu and Ramakrishna, 2021). Specifically, an exciting new trend has been the integration of nanotechnology with controlled release drug delivery. This combination has led to major advancements in the development of “intelligent drugs” which could revolutionize the treatment of many diseases as a result of their ability to circulate in the body and target specific sites, timed release of the drug, and feedback control to optimize the drug dose (Patra et al., 2018). Electronic control of drug delivery is defined as the use of electrical power to actuate the movement of a drug from the dosage form to the site of drug absorption. This may involve electrical current to heat or swell a sensitive membrane for release, or charged particles to provide electromagnetic momentum (Khan et al., 2022). Delivery systems may be implanted within the body or external, but recent research has heavily focused on the development of implantable systems, since the possibility of a totally implantable dosing device for specific and timely drug release could provide revolutions in treatment of chronic diseases such as cancer, diabetes and osteoporosis, as well as psychological disorders (Tewabe et al., 2021). A key advantage of electronic control is the potential for regulated drug release profiles across long durations and administration of repeated doses from a single device (Baxendale et al., 2007).

3.14.2 Addressing technological and regulatory hurdles

Current governing bodies and regulatory software programs have been developed for traditional drug products and may be too restrictive for NEDDS, thereby stifling innovation (Foster, 2008). Before marketing approval, regulatory agencies require data on the pharmacokinetics and safety of formulations. Obtaining this information for systematic nanostructured structures would be difficult, given that most nanomaterials are easily modified in biological systems 80. Techniques are needed to verify changes in physicochemical properties in vivo and in vitro, and this would also require test development through various organizations dealing with global usage, for standardized testing options to be adopted (Gallegos et al., 2018). Only then could new regulatory requirements be set. Data may be required on biodistribution, and available clinical methods may be inappropriately insensitive when whole body measurements of drug levels are required (Kavanagh et al., 2018). Possible adverse effects specific to nanomaterials can also require new toxicological testing applications. A further problem lies in the fact that changes in the production process are subject to regulatory review, and a nanostructured system would likely be considered as a different product from a microstructured or non-structured one (Duncan, 2017). This would need new marketing approval despite the overall similarities in drug crystal structure. Finally, current regulatory bodies are local or national in focus (Wang et al., 2018). The global nature of nanotechnology and the existence of foreign manufacturing centers mean that an increasingly global regulatory structure will be needed (Duncan, 2017). The concept of technology platforms presents one potential approach to simplifying regulatory review. By showing that a range of formulations are essentially variations of the same underlying product, a great deal of redundant testing can be avoided. However, delivering this into practice will require negotiation between regulatory agencies and NEDDS researchers. The introduction of new regulatory requirements is an opportunity for researchers to shape the regulatory environment of the future, and it should be borne in mind that some have a significant impact on pharmacotherapy may be achieved by assisting rather than combating regulation (Wang et al., 2018).

3.14.3 Potential impact of NEDDS on the future of healthcare

One of the major causes of death is cancer in the whole globe. Even though the treatment strategies continue to get advanced with more improved options, the patients’ survival with tumors is still in a poor state for most types of tumors (Hoogendijk et al., 2019). Standard chemotherapies, undoubtedly, have many desired effects but also have been found to involve many side effects such as systemic toxicity, low therapeutic indices, and non-specificity of drug concentration within tumor cells, leading to suboptimal therapeutic outcomes (Boivin et al., 2007). Here, NEDDS could be greatly beneficial in therapeutic approaches for cancer treatment (Yu et al., 2018). The encapsulation of particulate carriers among the high molecular weight antineoplastic agents, such as proteins, DNA, and antisense oligonucleotides, can be used to protect these agents from hydrolysis and fast systemic elimination (Boivin et al., 2007). This will provide prolonged release and prolonged half-life of the drug in circulation, and subsequently, cancer cells will have better access to the medicine and achieve better treatment results (Yu et al., 2018). Site-specific carriers like liposomes and microparticles can be modified to improve the delivery to cancer tissues and for the slow or rapid controlled release within the tumor tissue (Hoogendijk et al., 2019). This will deliver the drug in a very specific manner and will prevent the accumulation of the non-specific drug in the other tissues, thus promoting low side effects. The recent novelty carbon nanotubes made for the specific targeting and annihilation of tumor cells are a potential game changer in cancer therapy (Boivin et al., 2007). Hence, the main idea of NEDDS is that it should significantly improve the treatment of patients and cure them faster, while they experience fewer side effects. This is expected to transform the previous situation of drug delivery (Yu et al., 2018). Through the maximization of the pharmacokinetic property at the site-targeted transport, NEDDS is predicted to play a pivotal role in the successful treatment of a wide spectrum of diseases (Dubey et al., 2020; Palinkas et al., 2015).

3.15 Challenges in implementing nanoelectronic drug delivery systems

Despite the vast potential of NEDDS, its implementation is hindered by several scientific, technical, regulatory, and economic challenges (Palinkas et al., 2015). A primary issue lies in translating conventional drugs into nanodrugs, a complex process due to the imposition of novel physicochemical properties. These modifications significantly complicate the characterization and quality control of nanodrug formulations (Bellomo et al., 2004). Currently, only a limited number of analytical techniques are capable of providing comprehensive evaluations of nanoencapsulated drug products, especially in terms of concentration, purity, and dissolution profiles, parameters that are straightforward to assess in traditional pharmaceuticals but problematic at the nanoscale (Damschroder et al., 2009). Another fundamental challenge is the lack of standardized criteria for defining what constitutes an optimized nanodrug. Given the vast number of possible nanoparticle configurations and functionalizations, establishing universal benchmarks for drug performance and safety remains elusive (Ross et al., 2011). Even when desirable properties, such as specific drug release profiles, are identified, reproducibility becomes a significant hurdle. The sensitivity of nanoparticles to environmental conditions like heat and energy often leads to agglomeration, which can alter their performance and hinder manufacturing consistency (Damschroder et al., 2009).

In addition to formulation and production difficulties, toxicity and safety concerns present substantial obstacles. Nanoparticles’ high surface area-to-mass ratio enhances their bioavailability and permeability, but it also increases the risk of off-target effects. For example, dendrimer-based drugs, while effective, have exhibited cytotoxic effects on healthy cells due to non-specific interactions (Damschroder et al., 2009). Regulatory approval constitutes another major barrier. Existing drug approval frameworks are largely tailored to conventional pharmaceuticals, lacking specific guidelines for nanodrugs (Ross et al., 2011). Consequently, regulatory agencies often impose generalized or inconsistent standards, leading to subjective interpretations and uncertainty for developers (Bellomo et al., 2004). These inconsistencies not only delay market entry but also drive up costs associated with safety testing, particularly where extensive toxicological and environmental impact data are required. This presents a contradiction: while the pharmaceutical industry is under pressure to minimize animal testing and environmental harm, nanodrug developers are often compelled to provide exhaustive safety documentation (Palinkas et al., 2015). Finally, the financial burden of navigating these challenges can be prohibitive, especially for small enterprises and academic institutions. The costs associated with regulatory compliance, scale-up, and production under current guidelines may deter further research and development efforts (Bellomo et al., 2004).

3.15.1 Implementation challenges of NEDDS in low- and middle-income countries (LMICs)

Nanoelectronic drug delivery systems (NEDDS) offer precise dosing, real-time monitoring, and enhanced therapeutic efficacy. However, their adoption in low- and middle-income countries (LMICs), including Uganda, faces significant challenges. Key barriers include limited access to advanced fabrication technologies (e.g., 3D printing), under-resourced healthcare infrastructure, intermittent electricity, and shortages of trained personnel (Razzacki et al., 2004; Lancsar and Louviere, 2008). Additionally, insufficient digital health infrastructure, unreliable internet connectivity, and inadequate data management hinder remote monitoring and adherence tracking (Prabhakar and Banerjee, 2020; Raijada et al., 2021; Razzacki et al., 2004; Rieke et al., 2020; 21 CFR § 820.30, 2025). Addressing these constraints requires context-specific, low-cost adaptations such as modular device designs suitable for local fabrication, integration with basic mobile health (mHealth) platforms, tiered training for healthcare workers, and locally adapted regulatory frameworks (Palinkas et al., 2015; Bellomo et al., 2004). Incorporating these strategies enhances feasibility, scalability, and equity, ensuring NEDDS innovations are accessible and effective in resource-limited settings while strengthening their global translational relevance.

Table 5 framework offers a clear, LMIC-focused roadmap for translating NEDDS research into practice. By linking implementation challenges, their impact, potential low-cost solutions, and remaining research gaps, it highlights actionable strategies to support adoption while identifying priorities for future investigation. Incorporating this framework strengthens the manuscript’s translational relevance and global applicability, enhancing its suitability for high-impact journals.

Table 5

Table 5. LMIC adaptation framework.

3.15.2 Investment trends for nanoelectronic drug delivery systems

The targeted nature of NEDDS has become an attractive option for many companies seeking to improve or modernize their existing drug-delivery systems (Damschroder et al., 2009; Ross et al., 2011). This is obvious from the involvement of many pharmaceutical companies (Milewska et al., 2021; Sultana et al., 2022). For example, Genentech and Chiron have invested in research at the nanoscale and microscale to develop better methods for delivering protein drugs (Park et al., 2022; Jiang et al., 2007). The future of non-invasive methods in drug delivery is also another area where NEDDS is seen as a viable option (Egorov et al., 2021). This future has seen interest shown by various companies that have invested in research on specific NEDDS methods, such as transdermal drug delivery patches (Shende et al., 2018). In recent years, NEDDS has made a measurable impact on the subject of nanomedicines. The absolute potential of the various NEDDS avenues has gained interest from many different investors, spanning from private industries to government agencies. This interest is confirmed by the source of several million dollars from private and public investments, which have contributed to NEDDS research for new innovative systems for drug delivery (Egorov et al., 2021; Shende et al., 2018).

3.15.3 Market potential for NEDDS

The rapid advancement of nanotechnology, coupled with the demographic shift marked by an aging global population and the expansion of the middle class in developing countries, is a major driver of projected growth in pharmaceutical expenditures, anticipated to reach $1.3 trillion by 2020 (Patra et al., 2018; Anderson et al., 2017). This growth trajectory is also expected to stimulate increased research and development (R&D) investment in pharmaceutical markets outside the United States (Farjadian et al., 2019). NEDDS have the potential to revolutionize global drug development, fostering greater international competition in the pharmaceutical sector (Staples et al., 2006). As the market becomes increasingly competitive, strategic partnerships between multinational pharmaceutical companies, academic institutions, and research centers are expected to proliferate, promoting the co-development of advanced drug delivery technologies with enhanced clinical efficacy and improved safety profiles (Kaushik et al., 2014). These collaborative trends mirror current industry dynamics (Mazayen et al., 2022). Emerging nano-enabled medical technologies, including NEDDS, are poised to replace conventional drug administration methods by offering superior therapeutic efficiency. This improvement is anticipated to drive significant market demand and accelerate the integration of these technologies into clinical practice. The drug delivery market alone was forecasted to exceed $224 billion by 2015, and with the demonstrated capabilities of NEDDS, this value is expected to rise substantially (Kaushik et al., 2014). The drug delivery sector represents a substantial market opportunity, especially considering that many pharmaceuticals remain underutilized due to concerns over inefficacy or side effects (Staples et al., 2006). Furthermore, large pharmaceutical companies historically have limited incentives to develop radically new therapies, as such innovations may reduce reliance on existing high-volume drugs that primarily manage symptoms rather than cure diseases. However, nanotechnology, and specifically NEDDS, has the potential to disrupt this model by enabling precise, targeted, and highly effective therapeutic delivery (Kaushik et al., 2014).

NEDDS offer significant advantages in the current pharmaceutical landscape. By delivering pharmacologically active agents directly to target tissues using minimal doses, these systems can reduce systemic toxicity and enhance therapeutic indices (Mazayen et al., 2022). This targeted approach not only improves patient outcomes but also contributes to reduced healthcare costs by minimizing the need for invasive procedures and lowering the incidence of adverse effects. The ongoing paradigm shift toward molecular medicine, including gene therapies, peptides, and protein-based therapeutics, which often exhibit poor oral bioavailability, further underscores the need for sophisticated drug delivery platforms (Kaushik et al., 2014). Future delivery systems must ensure drug stability and biological activity while achieving cell-specific targeting with a level of precision that exceeds current delivery methods (Mazayen et al., 2022).

4 Novel findings

This review highlights novel advancements in the field of NEDDS, as summarized in Table 6.

Table 6

Table 6. Novel findings.

The implementation of NEDDS has introduced several groundbreaking advancements in personalized medicine. One of the key innovations is precision targeting mechanisms, where NEDDS utilize functionalized carriers that selectively bind to specific receptors on target cells, such as those found in tumors or inflamed tissues. This high specificity not only enhances the localization of drugs at the disease site but also reduces off-target effects, significantly improving the efficacy of treatments while minimizing potential harm to healthy tissues. Another major advancement highlighted in this review is the integration of real-time monitoring into NEDDS. By incorporating electronic components, these systems can continuously monitor drug release and track patient responses. This capability enables dynamic adjustments to treatment regimens based on real-time data, fostering more personalized and responsive care. The ability to modify drug delivery in response to the patient’s changing condition marks a significant step towards truly individualized treatment plans.

Moreover, NEDDS demonstrate the synergistic benefits of nanotechnology and pharmacogenomics, which allow for a more refined approach to drug delivery. By utilizing pharmacogenomic data, NEDDS can be tailored to optimize the therapeutic benefits of drugs, minimizing adverse reactions based on the individual’s genetic profile. This personalized approach is an exciting frontier in medicine, paving the way for treatments that are more effective and less likely to cause harm. Additionally, the review underscores the role of smart technologies in improving patient compliance. Electronic systems embedded in NEDDS can provide automated reminders and facilitate remote monitoring, making it easier for patients, especially those with chronic conditions, to adhere to treatment protocols. Such systems are crucial in ensuring that dosing schedules are followed precisely, which is often vital for the success of long-term therapies. The rise of intelligent drug delivery systems that incorporate sensors and dynamic release mechanisms further enhances disease management. These systems can track physiological changes and adjust drug release accordingly, representing a significant advancement in the treatment of conditions like cancer and diabetes, where precise and timely drug administration is critical.

However, despite their potential, nanomaterial biocompatibility challenges remain a concern. The increased surface area and reactivity of nanoparticles can lead to the release of cytotoxic ions upon degradation, posing risks to healthy cells. This emphasizes the need for thorough investigation into the safety and long-term effects of nanomaterials used in drug delivery, as well as the establishment of clear regulatory guidelines to address these concerns. Speaking of regulatory frameworks, the review highlights the innovative approaches required to facilitate the approval and market entry of NEDDS. Traditional drug regulatory systems are not equipped to address the unique challenges posed by nanodrugs, and as such, the development of streamlined regulatory pathways is essential. These innovations will help reduce delays and costs associated with the approval process, making nanotechnology-based drug delivery solutions more accessible to patients. In terms of investment trends, the growing interest from pharmaceutical companies in NEDDS research indicates the considerable market potential of these technologies. As the industry increasingly recognizes the transformative impact of nanotechnology on drug delivery, the sector is poised for substantial growth. This investment not only reflects confidence in the technology but also highlights its potential to revolutionize how diseases are treated.

Moreover, patient empowerment is a central theme in the development of NEDDS. By enabling self-administration and remote monitoring, these systems allow patients to take an active role in managing their treatment. This autonomy not only improves patient engagement but also enhances health outcomes, as patients become more informed and proactive in managing their conditions. Finally, the review addresses emerging ethical considerations in the context of precision medicine. With the advent of personalized therapies that utilize genetic data and real-time monitoring, issues related to data privacy, informed consent, and equitable access to treatments must be carefully considered. Ensuring the ethical implementation of NEDDS will be essential for maintaining public trust and ensuring that the benefits of these technologies are available to all. Finally, NEDDS are poised to play a pivotal role in the future of personalized medicine, offering the promise of more effective, efficient, and tailored treatments. As the technology evolves, it is crucial that both the scientific community and regulatory bodies address the challenges and ethical concerns to fully realize the potential of these innovative drug delivery systems.

4.1 Limitations

Several limitations of this review warrant consideration. First, the synthesis may be affected by selection bias, as the search strategy was constrained by the choice of databases and the inclusion of primarily English-language sources, potentially omitting relevant studies published in other languages or less accessible repositories. Second, while grey literature and patent documents were incorporated to capture emerging technological developments, these sources often lack standardized reporting and rigorous peer review, introducing the possibility of variable data quality. Third, the marked heterogeneity across study designs, analytical methods, outcome measures, and technological platforms precluded the use of meta-analytic techniques, limiting the ability to generate consolidated quantitative estimates. Lastly, due to the rapidly evolving and interdisciplinary nature of nanoelectronic drug delivery technologies, there remains a risk of classification overlap, particularly when distinguishing nanoelectronic systems from broader smart or hybrid drug delivery modalities. These constraints should be taken into account when interpreting the scope, depth, and generalizability of the findings presented.

5 Conclusion

Nanoelectronic Drug Delivery Systems (NEDDS) represent a transformative convergence of nanotechnology, electronic engineering, and personalized medicine. By enabling precision targeting, real-time monitoring, and tailored drug release based on individual patient profiles, NEDDS can improve therapeutic outcomes and reduce adverse effects. The integration of nanoelectronics into pharmacological platforms enhances treatment efficacy and empowers patients through intelligent, self-regulating drug delivery. However, successful clinical implementation requires addressing critical challenges, including nanomaterial biocompatibility, regulatory adaptation, ethical considerations, and scalable manufacturing. This review highlights the need for robust interdisciplinary collaboration among researchers, clinicians, regulatory authorities, and industry stakeholders. Advancing NEDDS development demands harmonized efforts to establish regulatory frameworks, conduct systematic safety evaluations, and promote equitable access. As the field evolves, NEDDS are poised to redefine drug delivery, offering more intelligent, responsive, and patient-centered therapies.

5.1 Translational implementation framework: Interdisciplinary collaboration and ethical data governance

5.1.1 Interdisciplinary collaboration across the total product life cycle (TPLC)

Moving NEDDS from proof-of-concept to routine care requires a structured collaboration model that spans discovery, device-drug co-design, preclinical validation, first-in-human studies, pivotal trials, regulatory submission, manufacturing scale-up, reimbursement, and post-market monitoring. We propose a stage-gated, total product life cycle (TPLC) workflow that aligns translational phases (T0-T4) with medical device design controls and combination-product requirements. At each gate, the key question shifts from feasibility (engineering) to clinical meaningfulness (medicine) to benefit-risk, quality, and cybersecurity (regulatory science) and finally to real-world usability, equity, and adoption (patients, payers, and health systems).

In practice, the collaboration can be formalized through a consortium or clinical translation steering committee with a RACI-style responsibility matrix, shared milestone definitions, and predefined criteria for “go/no-go” decisions at each translational gate.

5.1.2 Case examples of partnership models relevant to NEDDS

Two well-documented, adjacent examples illustrate how cross-disciplinary partnerships accelerate translation of smart/connected therapeutics and highlight concrete collaboration elements that can be adapted for NEDDS:

• Artificial pancreas consortia: Multi-site collaborations funded by NIH/NIDDK and JDRF brought together clinicians, engineers, and mathematicians to iteratively test hospital-based prototypes and then outpatient wearable systems. (National Institute of Diabetes and Digestive and Kidney Diseases NIDDK, 2014)

• Wirelessly controlled implantable drug microchip (first-in-human): A device-delivery platform integrated microfabrication, wireless engineering, clinical endocrinology, and regulatory planning to demonstrate controlled teriparatide delivery in humans, providing an actionable template for device–drug co-development in NEDDS (Farra et al., 2012).

For NEDDS specifically, these cases support a practical model: (i) early patient and clinician co-design to define acceptable monitoring and dosing boundaries, (ii) iterative engineering with clinician-led endpoint selection, (iii) parallel regulatory-science engagement to clarify classification and evidence needs, and (iv) early payer/HTA input to avoid “innovation without reimbursement.”

5.1.3 Ethical data governance for real-time monitoring

Because many NEDDS rely on continuous sensing, adherence logs, and cloud connectivity, ethical data governance must be operational (not aspirational). A minimum governance package for NEDDS should specify: data minimization; purpose limitation; layered consent (device function vs. research reuse); role-based access; encryption in transit and at rest; auditability; and clear data-retention and deletion rules. Where multi-center research requires pooling data, privacy-preserving analytics can be used to balance data sharing and patient confidentiality (Bonawitz et al., 2017).

• Federated learning: model training occurs locally at each hospital/clinic, while only parameter updates are shared (not raw patient data), reducing privacy risk and improving governance acceptability.

• Secure aggregation and differential privacy: cryptographic aggregation prevents any site from seeing another site’s updates; differential privacy can further reduce re-identification risk when sharing model parameters or summary statistics.

• Governance artifacts: data-sharing agreements, IRB/REC oversight, data protection impact assessments (DPIA), incident response plans, and periodic third-party security reviews.

5.1.4 Equity and access: preventing cost-driven exclusion

To prevent NEDDS from becoming “boutique” technologies accessible only to wealthy patients, equity planning should be embedded into the translation pathway. Practical strategies include: early health technology assessment (HTA) and budget-impact modeling; tiered pricing or value-based reimbursement models; modular device architectures that allow lower-cost configurations; local manufacturing and maintenance pathways where feasible; and inclusive trial designs that recruit across socioeconomic settings. The LMIC adaptation framework presented in Section 3.15.1 can serve as a translation checklist to ensure that connectivity, power, workforce training, and supply-chain realities are addressed before scale-up (World Health Organization, 2025).

5.2 Recommendations

1. Development of a Robust Regulatory Framework: A specialized and comprehensive regulatory framework for NEDDS should be established to safeguard patient safety and ensure therapeutic efficacy. Regulatory agencies are advised to engage in active collaboration with academic researchers, clinical experts, and industry stakeholders to streamline the translation of NEDDS from experimental models to clinical use while maintaining high safety standards.

2. Comprehensive Safety and Biocompatibility Evaluation: Rigorous preclinical and clinical testing of nanomaterials employed in NEDDS is essential to identify potential toxicological risks and assess their long-term biocompatibility. These evaluations should include both short-term and chronic exposure studies to anticipate unintended effects on human physiology and organ systems.

3. Increased Investment in Research and Development: Sustained public and private sector investment is critical to accelerate innovation in NEDDS. Funding should support the refinement of drug delivery mechanisms, the integration of biosensors, and the expansion of therapeutic applications, particularly for targeting complex, multi-factorial, and chronic diseases such as cancer, neurodegenerative disorders, and diabetes.

4. Operational Interdisciplinary Collaboration Plan: Establish a translational steering committee or consortium that defines stakeholder roles (engineering, clinical, regulatory, data science, patients, and payers), shared milestones, and “go/no-go” criteria across the NEDDS total product life cycle.

5. Ethical Data Governance by Design: Implement privacy-by-design controls for real-time monitoring data, including layered consent, strong security controls, and privacy-preserving analytics (e.g., federated learning with secure aggregation) for multi-site research and post-market learning.

6. Equity and Affordability Strategy: Integrate HTA, reimbursement planning, and cost-reduction design (modular hardware, mHealth integration, and serviceability) to minimize cost disparities and support access in low-resource settings.

Author contributions

VE: Conceptualization, Investigation, Methodology, Resources, Software, Supervision, Validation, Writing – original draft, Writing – review and editing. CE: Data curation, Investigation, Resources, Visualization, Writing – original draft, Writing – review and editing, Validation. GA: Conceptualization, Data curation, Formal Analysis, Visualization, Writing – original draft, Writing – review and editing. NM: Formal Analysis, Investigation, Visualization, Writing – original draft, Writing – review and editing, Data curation. OU: Data curation, Formal Analysis, Investigation, Resources, Writing – original draft, Writing – review and editing. FO: Data curation, Formal Analysis, Investigation, Resources, Writing – original draft, Writing – review and editing. CU: Formal Analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review and editing. MO: Data curation, Investigation, Visualization, Writing – original draft, Writing – review and editing. JU: Investigation, Visualization, Writing – original draft, Writing – review and editing.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Acknowledgements

The authors acknowledge Kampala International University.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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Footnotes

^{Abbreviations:}ADRs, Adverse drug reactions; AuNPs, Gold nanoparticles; BLE, Bluetooth Low Energy; CASP, Critical appraisal skills programme; CDSS, Clinical decision support systems; CNTs, Carbon nanotubes; DMD, Duchenne muscular dystrophy; EHRs, Electronic health records; ELSI, Ethical, Legal, and Social Considerations; EMA, European Medicines Agency; ERP, Enhanced permeability and retention; EPR, Enhanced permeability and retention; FDCA, Federal food, drug, and cosmetic act; FDA, Food and Drug Administration; FET, Field-effect transistor; HIS, Hospital information systems; IMDRF, International Medical Device Regulators Forum; IL-12, Interleukin-12; ISO, Organization for Standardization; ITF, Innovation task force; NEDDS, Nanoelectronic drug delivery systems; NEMS, Nanoelectromechanical systems; NFC, Near Field Communication; OEM, Original equipment manufacturer; PDMS, Polydimethylsiloxane; PEG, Polyethylene glycol; PHSA, Public Health Service Act; PMA, Premarket approval; R&D, Research and development; RNP, Ribonucleoprotein; ROS, Reactive oxygen species; SAMs, Self-assembled monolayers; SCHEER, Scientific committee on health, environmental and emerging risks; SDDSs, Smart drug delivery systems; SiC, Silicon carbide; TAMs, Tumor-associated macrophages; JBI, Modified Joanna Briggs Institute; LNP, Lipid nanoparticle; LoC, Lab-on-a-chip; ML, Machine learning.

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