Use Of Nanorobots in The Treatment of Cancer

1. 1. Global Burden of Cancer

Cancer is one of the most significant health challenges of the 21st century. According to the World Health Organization (WHO), it is the second leading cause of death globally, with nearly 10 million deaths in 2020 alone [1]. The most prevalent cancers include lung, breast, colorectal, prostate, and liver cancers, which together contribute to the majority of cancer-related deaths. Rapid urbanization, aging populations, lifestyle changes, and genetic predispositions are further driving cancer incidence worldwide [2]. The increasing healthcare burden underscores the urgent need for novel and more effective therapeutic strategies.

1. 2. Limitations of Conventional Cancer Therapies

Despite advances in medical science, conventional cancer treatments such as surgery, chemotherapy, radiotherapy, and immunotherapy face critical challenges:

1. Lack of specificity: Chemotherapy and radiotherapy affect both cancerous and normal cells, resulting in systemic toxicity.
2. Drug resistance: Many tumors develop multidrug resistance (MDR), reducing the efficacy of standard treatments [3].
3. Recurrence and metastasis: Even after initial remission, many cancers recur, often more aggressively.
4. Severe side effects: Patients often suffer from nausea, hair loss, fatigue, organ toxicity, and compromised immunity [4].
   These limitations highlight the need for therapies that are more targeted, efficient, and minimally invasive.
   3. Emergence of Nanotechnology in Medicine

Over the past two decades, nanotechnology has revolutionized the biomedical field. Nanomedicine, which employs nanoscale materials such as nanoparticles, liposomes, micelles, and dendrimers, has already improved drug solubility, circulation times, and tumor targeting [5]. Examples include FDA-approved nanoparticle-based drugs such as Doxil® (liposomal doxorubicin) and Abraxane® (albumin-bound paclitaxel), which demonstrate how nanoscale systems can enhance cancer treatment outcomes [6]. Building upon these advancements, the integration of nanorobotics represents a next-generation step in cancer therapy.

1. 4. Concept of Nanorobots

Nanorobots are nanoscale machines capable of performing specific tasks at the cellular and molecular level [7]. They are typically fabricated from biocompatible materials such as carbon nanotubes, DNA origami, or metallic nanostructures and can be engineered to detect, navigate, and eliminate cancer cells with high precision [8]. Controlled by external stimuli (magnetic fields, ultrasound, light, or chemical gradients) or pre-programmed molecular logic gates, nanorobots can serve as autonomous therapeutic agents. Their potential lies in integrating diagnosis, therapy, and monitoring into a single nanosystem.

1. 5. Scope of Nanorobots in Oncology

Nanorobots have demonstrated wide-ranging applications in oncology, with particular promise in early detection, therapy, and long-term monitoring. They can identify tumor-specific biomarkers at very low concentrations, thereby enabling early diagnosis and timely intervention. For treatment, nanorobots are capable of transporting drugs directly to tumor sites, significantly reducing systemic toxicity compared to conventional chemotherapy. Another important application lies in overcoming multidrug resistance (MDR); by bypassing efflux pumps or co-delivering resistance modulators, nanorobots can restore the sensitivity of resistant cancer cells. Furthermore, they have the potential to modulate the tumor microenvironment by addressing challenges such as hypoxia, acidity, or stromal barriers, thereby improving therapeutic response. Beyond single modalities, nanorobots facilitate combination therapies, including synergistic approaches such as chemotherapy combined with photothermal or gene therapy. Finally, nanorobots can provide continuous post-treatment surveillance, detecting recurrence or metastasis at early stages through integrated diagnostic capabilities [9,10].

1. 6. Objectives of the Review

The main objectives of this review are:

1. To provide a comprehensive overview of nanorobotics and their biomedical foundations.
2. To explain the design, functional mechanisms, and navigation strategies of nanorobots in cancer therapy.
3. To summarize applications of nanorobots in cancer detection, drug delivery, and treatment.
4. To highlight recent advances, case studies, and ongoing research in this emerging field.
5. To critically analyze the current challenges, limitations, and ethical concerns associated with nanorobot-based therapy.
6. To discuss future directions and the potential of nanorobots in achieving personalized and precision oncology.

2. Fundamentals of Nanorobotics

Nanorobotics is an interdisciplinary field combining nanotechnology, robotics, materials science, and biomedical engineering. It focuses on the design and application of nanoscale machines or robots that can perform precise tasks at the cellular or molecular level [11]. In oncology, nanorobots are envisioned as intelligent devices capable of navigating through biological environments, detecting malignant cells, and delivering therapeutic payloads directly to tumor sites with minimal collateral damage.

1. 1. Definition of Nanorobots in Medical Applications

Nanorobots are artificially engineered nanoscale devices, typically ranging from 1–1000 nm, designed to carry out medical tasks such as diagnosis, drug delivery, tissue repair, and real-time monitoring [12]. In the context of cancer therapy, they can be programmed with highly specific functions that enhance precision and therapeutic efficiency. These include the detection of tumor-specific biomarkers, such as overexpressed receptors or circulating DNA and RNA fragments, which enable early and accurate diagnosis. Nanorobots can also selectively deliver drugs or biomolecules to malignant cells, thereby minimizing systemic toxicity and improving treatment outcomes. In addition, they are capable of inducing localized therapeutic effects such as hyperthermia or photothermal therapy, which further enhances cancer cell eradication while sparing healthy tissue. Importantly, nanorobots can also serve as diagnostic tools by reporting real-time information about tumor progression or therapeutic response, providing an integrated approach to both treatment and monitoring [13].

1. 2. Size, Structure, and Material Composition

The design of nanorobots depends heavily on biocompatible and biodegradable materials to ensure safety and efficiency.

• Size: typically in the range of 1–1000 nm to allow circulation in the bloodstream, tissue penetration, and cellular uptake [14].
• Materials used:
  • Carbon-based nanostructures (carbon nanotubes, graphene) for strength and electrical properties [15].
  • DNA origami: self-assembling DNA structures that fold into programmable 3D shapes [16].
  • Polymeric nanostructures: PEG, PLGA, chitosan for drug encapsulation and biocompatibility.
  • Metallic nanostructures: gold, silver, and iron oxide for imaging and magnetic guidance [17].
  • Biological membranes: coating nanorobots with cell membranes (e.g., red blood cells, leukocytes) for immune evasion and longer circulation times [18].

1. 3. Types of Nanorobots

Different classes of nanorobots have been developed depending on their design and function:

1. Bio-inspired nanorobots are engineered to replicate the natural structure and function of microorganisms such as bacteria, flagella, or immune cells. They use biological propulsion systems like flagellar motion to navigate effectively through the human body. By mimicking natural motility, these nanorobots can move efficiently in biological fluids and tissues, which makes them suitable for targeted cancer therapy applications [19].
2. DNA-based nanorobots are constructed using DNA origami technology, where DNA strands fold into specific three-dimensional structures. These programmable nanorobots can open and close in response to molecular triggers, enabling precise and controlled drug release. A notable example is the use of DNA nanorobots to deliver thrombin directly into tumor vasculature, leading to localized clot formation and suppression of tumor growth without affecting healthy tissues [20].
3. Magnetically controlled nanorobots contain magnetic nanoparticles that allow them to be directed by external magnetic fields. This non-invasive control strategy enables deep tissue penetration and precise navigation toward tumors. Such systems offer significant potential for targeted cancer therapy by enhancing drug accumulation at specific sites while minimizing systemic side effects [21].
4. Chemical or enzymatic nanorobots rely on local fuels such as hydrogen peroxide, glucose, or urea to generate propulsion. These systems are particularly useful in tumor environments, which often exhibit distinct chemical features such as low pH or high enzymatic activity. By exploiting these unique microenvironmental conditions, chemical and enzymatic nanorobots can achieve selective activation and improved therapeutic specificity [22].
5. Hybrid nanorobots combine synthetic nanostructures with natural biological components such as bacteria, stem cells, or immune cells. This hybrid approach takes advantage of the adaptability and tumor-homing capabilities of living cells, while also leveraging the precision and programmability of engineered materials. As a result, hybrid nanorobots provide enhanced biocompatibility, deeper tumor penetration, and multifunctional therapeutic potential compared to purely synthetic systems [23].

Fig: Types of Nanorobots

Nanorobots require precise control mechanisms to reach tumor sites without affecting normal tissues. Current navigation strategies include:

1. Magnetic field-based navigation

 is one of the most widely studied approaches for controlling nanorobots. In this method, nanorobots are embedded with magnetic nanoparticles such as iron oxide, which respond to external magnetic fields. By applying controlled magnetic gradients, researchers can steer these nanorobots with high precision toward tumor sites, even in deep tissue regions, in a non-invasive manner. This allows for improved accuracy of drug delivery while minimizing collateral damage to healthy cells [24].

2. Chemical gradients (chemotaxis)

provide another strategy for guiding nanorobots within the tumor microenvironment. Tumors are known to release specific metabolites, such as lactate, and exhibit conditions like acidic pH. Nanorobots can be engineered to sense and follow these biochemical signals, enabling autonomous movement toward cancerous tissue. This chemotactic navigation mimics natural cellular behavior and offers the advantage of selective accumulation at the diseased site [25].

3. Ultrasound-based propulsion

uses acoustic waves to generate thrust and direct nanorobot movement in biological tissues. When exposed to ultrasound, nanostructures can oscillate or vibrate, producing mechanical forces that propel them forward. This approach not only enables non-invasive control but also benefits from ultrasound’s ability to penetrate deeply into the body, making it suitable for clinical applications such as targeted drug delivery and localized therapy [26].

4. Light-based control

employs near-infrared (NIR) or ultraviolet (UV) light to activate or guide nanorobots in specific tissues. NIR light, in particular, has good tissue penetration and can trigger photothermal effects, enabling the nanorobots to release therapeutic payloads in a controlled, site-specific manner. UV light, although less penetrative, can provide precise control in superficial tumors. This optical approach combines spatial accuracy with the possibility of activating nanorobots on demand [27].

5. Biological propulsion

harnesses the natural motility of living systems to drive nanorobots. Engineered bacteria, sperm cells, or enzymes can generate autonomous movement within the human body. For example, magnetotactic bacteria can migrate along magnetic field lines, while enzymatic reactions with local fuels like glucose or urea can generate thrust. These biohybrid or enzyme-driven strategies offer the advantage of natural adaptability and enhanced biocompatibility compared to fully synthetic propulsion systems [28].

1. 5. Significance of Fundamentals in Oncology

Understanding the basic principles of size, materials, types, and navigation strategies is essential for applying nanorobots in cancer treatment. These parameters directly influence:

• Circulation time in the bloodstream.
• Tumor accumulation through passive (EPR effect) or active targeting.
• Biocompatibility and clearance from the body.
• Efficiency of drug delivery and therapeutic outcomes [29].

3. Design and Functional Mechanisms of Nanorobots in Cancer Therapy

The design of nanorobots for cancer treatment requires the integration of multiple functional components: targeting elements, therapeutic payloads, navigation systems, and diagnostic modules. These systems must work in synergy to ensure precision drug delivery, minimal toxicity, and effective tumor eradication [30].

1. 1. Targeting Strategies

Effective targeting of cancer cells is the cornerstone of nanorobot design. Two main approaches exist:

• • • Passive Targeting

Relies on the Enhanced Permeability and Retention (EPR) effect, where leaky tumor vasculature allows nanorobots or nanoparticles to accumulate preferentially in tumors [31].Passive targeting increases drug concentration at tumor sites compared to normal tissues but lacks specificity for individual cancer cell populations [32].

• Active Targeting

Achieved by attaching ligands, antibodies, peptides, or aptamers on nanorobot surfaces that specifically bind to overexpressed receptors on tumor cells [33].

Examples include:

• • Folic acid-conjugated nanorobots targeting folate receptors in ovarian cancer.
  • HER2 antibody-modified nanorobots for breast cancer therapy.
  • Aptamer-based nanorobots recognizing nucleolin in glioblastoma [34,35].

1. 2. Controlled Drug Delivery Mechanisms

Nanorobots offer spatial and temporal control over therapeutic release, minimizing systemic side effects.

• Precision Delivery

• Nanorobots can deliver chemotherapeutic agents directly to tumor cells while sparing healthy tissues.
• Example: Doxorubicin-loaded nanorobots releasing drugs only within acidic tumor environments [36].

• Stimuli-Responsive Release

• pH-sensitive systems: exploit acidic tumor microenvironments for drug release.
• Temperature-sensitive systems: release payloads under hyperthermia conditions.
• Enzyme-triggered release: respond to tumor-associated enzymes like MMPs (matrix metalloproteinases) [37].
• Externally triggered release: controlled by magnetic fields, ultrasound, or light [38].
  3. Tumor Detection and Diagnostics

Beyond therapy, nanorobots can act as diagnostic biosensors, enabling early detection and real-time monitoring:

• Biomarker detection: Nanorobots functionalized with probes detect proteins (e.g., PSA, CEA), nucleic acids, or exosomes [39].
• Imaging agents: Magnetic or gold-based nanorobots enhance MRI, PET, or optical imaging for tumor localization [40].
• Smart biosensing nanorobots: capable of reporting tumor progression or treatment response in vivo [41].
  4. Therapeutic Modalities Enabled by Nanorobots

Nanorobots are versatile and can integrate multiple therapeutic approaches:

• Chemotherapy Delivery

Nanorobots can be engineered to encapsulate cytotoxic drugs such as doxorubicin and cisplatin, which are widely used in conventional chemotherapy. By delivering these agents directly to tumor sites, nanorobots ensure localized drug release while minimizing systemic distribution. This approach significantly reduces adverse effects commonly associated with chemotherapy, such as cardiotoxicity, nephrotoxicity, and immunosuppression, while simultaneously improving therapeutic efficacy. As a result, nanorobotic-assisted chemotherapy represents a major advancement over free-drug administration in terms of safety and precision [42].

• Gene Therapy

Another promising application of nanorobots lies in the delivery of genetic material, including DNA, siRNA, and CRISPR-Cas9 systems. These nanodevices can transport gene-editing tools to cancer cells to silence oncogenes, repair mutations, or reprogram cellular functions. For example, siRNA-loaded nanorobots targeting the KRAS mutation in pancreatic cancer have demonstrated potential in selectively inhibiting tumor growth by suppressing key oncogenic pathways. This ability to provide site-specific and controlled delivery of genetic therapeutics makes nanorobots valuable tools for advancing cancer gene therapy [43].

• Immunotherapy Enhancement

Nanorobots also hold great potential in augmenting cancer immunotherapy. They can deliver immune checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4 antibodies, or cytokines directly to the tumor microenvironment. This targeted delivery improves immune activation against cancer cells while reducing systemic immune-related toxicities. Additionally, nanorobots may present tumor-associated antigens to the immune system, thereby enhancing antigen recognition and stimulating a stronger, more durable anti-tumor immune response. Such strategies can overcome resistance and improve patient outcomes in immunotherapy [44,45].

• Photothermal and Photodynamic Therapy
  Nanorobots composed of materials like gold nanoparticles or carbon-based nanostructures can be used in light-activated therapies. In photothermal therapy, nanorobots absorb near-infrared (NIR) light and convert it into heat, causing localized hyperthermia that selectively destroys cancer cells [46]. Alternatively, in photodynamic therapy, nanorobots generate reactive oxygen species (ROS) upon exposure to specific wavelengths of light, inducing oxidative stress and apoptosis in tumor cells Both approaches are minimally invasive and offer precise, on-demand cancer treatment with limited damage to healthy tissues. [47].

Fig: Nanorobot Function Mechanism in Cancer Therapy

Modern nanorobot designs often combine multiple features into a theranostic platform (therapy + diagnostics). For instance:

• A single DNA nanorobot may detect tumor biomarkers, deliver a chemotherapeutic payload, and simultaneously allow imaging for therapy monitoring [48].
• Such multifunctionality highlights the transformative potential of nanorobots in precision oncology.

4. Applications of Nanorobots in Cancer Treatment

Nanorobots represent a new generation of therapeutic platforms capable of integrating diagnosis, therapy, and monitoring within a single nanosystem. Their applications in cancer treatment extend across the entire clinical spectrum—from early detection and diagnosis to treatment, prevention of metastasis, and post-therapy monitoring [49].

1. 1. Early Detection and Diagnosis of Tumours

Early detection significantly improves survival outcomes in cancer. Nanorobots offer several diagnostic advantages:

• Biomarker detection: Nanorobots can be functionalized with probes to detect proteins (e.g., PSA, CEA), circulating tumor DNA (ctDNA), or exosomes in blood [50].
• Imaging enhancement: Metallic or magnetic nanorobots enhance MRI, PET, and optical imaging, improving tumor visualization [51].
• In vivo biosensors: Smart nanorobots provide real-time information on tumor growth and therapeutic responses [52].

Example: DNA origami nanorobots loaded with molecular beacons have been used for detecting microRNA biomarkers of breast cancer [53].

1. 2. Targeted Drug Delivery

One of the most promising applications is the precise delivery of chemotherapy agents directly to tumor sites.

• Reduced toxicity: Drugs are released only at the tumor site, minimizing systemic side effects [54].
• Higher efficacy: Localized concentration of drugs improves therapeutic outcomes.
• Deep penetration: Nanorobots can navigate through dense tumor stroma and hypoxic regions [55].

Example: pH-sensitive doxorubicin-loaded nanorobots were demonstrated to release the drug selectively in acidic tumor microenvironments [56].

1. 3. Elimination of Circulating Tumor Cells (CTCs)

Metastasis is responsible for over 90% of cancer-related deaths [57]. Nanorobots can actively patrol the bloodstream to:

• Identify and capture CTCs via ligand-receptor interactions.
• Deliver cytotoxic agents to eliminate CTCs before they colonize distant organs.

Example: Magnetic nanorobots coated with epithelial cell adhesion molecule (EpCAM) antibodies showed efficiency in binding and removing CTCs in preclinical models [58].

1. 4. Overcoming Multidrug Resistance (MDR)

Resistance to chemotherapy is a major limitation in cancer therapy. Nanorobots can overcome MDR by:

• Delivering drugs directly into the cytoplasm, bypassing efflux pumps.
• Co-delivering MDR inhibitors along with chemotherapeutics [59].
• Targeting hypoxic niches, where drug resistance is typically higher [60].

Example: Hybrid nanorobots co-delivering doxorubicin and P-glycoprotein inhibitors improved sensitivity of resistant breast cancer cells [61].

1. 5. Tumor Microenvironment Modulation

The tumor microenvironment (TME) is often hypoxic, acidic, and immune-suppressive. Nanorobots can:

• Normalize tumor vasculature to improve drug penetration.
• Deliver oxygen or oxygen-generating agents to overcome hypoxia [62].
• Release immunomodulators to reprogram tumor-associated macrophages (TAMs) from pro-tumor (M2) to anti-tumor (M1) phenotypes [63].
  6. Combination Therapies

Nanorobots can integrate multiple therapies into a single platform:

• Chemo + Gene therapy: Simultaneous delivery of doxorubicin and siRNA targeting oncogenes [64].
• Chemo + Immunotherapy: Co-delivery of chemotherapy drugs with checkpoint inhibitors (anti-PD-1, anti-CTLA-4).
• Chemo + Photothermal/Photodynamic therapy: Nanorobots loaded with gold nanoparticles can release drugs and simultaneously induce hyperthermia upon NIR laser irradiation [65].

Example: DNA origami nanorobots delivering both chemotherapy drugs and CpG oligonucleotides successfully combined chemotherapy with immune stimulation in melanoma models [66].

1. 7. Post-Treatment Monitoring and Recurrence Prevention

Nanorobots may act as surveillance systems after therapy:

• Detecting minimal residual disease (MRD).
• Providing early warning of recurrence.
• Monitoring therapeutic response in real time [67].

Example: Smart biosensing nanorobots capable of reporting tumor recurrence through fluorescence signaling have been tested in preclinical models [68].

4.8 Clinical Outlook

While most nanorobot applications remain in preclinical or experimental stages, rapid progress is being made. Ongoing research indicates that nanorobots may soon be applied in:

• Personalized medicine: patient-specific tumor targeting.
• Theranostics: simultaneous diagnosis and therapy.
• Minimally invasive oncology: replacing systemic chemotherapy with precision nanorobotic interventions [69,70].

A number of preclinical studies have demonstrated the potential of nanorobots in cancer therapy. One of the most significant breakthroughs was reported by Li et al., who designed DNA origami-based nanorobots capable of carrying thrombin and releasing it selectively within tumor vasculature. This caused localized clot formation, cutting off blood supply and significantly inhibiting tumor growth in mice without harming normal tissues [71]. Similarly, Xu et al. developed magnetically guided helical nanorobots that could be loaded with chemotherapeutics and precisely steered to tumors using external magnetic fields. Their results confirmed enhanced drug accumulation and improved therapeutic efficacy compared to free drugs [72]. Gao et al. further introduced enzyme-propelled nanorobots powered by urease, enabling them to actively penetrate gastric mucosa and deliver therapeutic agents. While initially applied to bacterial infections, this approach has been adapted to gastric cancer therapy, showcasing the adaptability of enzyme-powered nanorobots [73]. Biohybrid systems also represent a promising direction; Felfoul et al. demonstrated that magnetotactic bacteria carrying drug-loaded liposomes could autonomously migrate toward hypoxic tumor regions, a major challenge in oncology due to resistance to conventional therapies [74]. Together, these preclinical investigations highlight the feasibility of nanorobots in achieving targeted delivery, precise tumor penetration, and environment-responsive therapy.

1. 2. Early Clinical Progress

While nanorobot applications remain primarily in experimental phases, important steps toward clinical translation have been made. For example, Medina-Sánchez et al. reported that cell-based micromotors could be successfully tested in large animals such as pigs and rabbits, demonstrating targeted navigation and drug delivery within vascular networks [75]. These findings suggest that nanorobot-based approaches may be scalable to human applications. Furthermore, researchers are increasingly integrating artificial intelligence (AI) and machine learning into nanorobotics, enabling enhanced control, autonomous navigation, and patient-specific therapeutic planning [76]. Although no nanorobot-based therapies have yet reached FDA approval, the convergence of nanotechnology, AI, and bioengineering provides a strong foundation for the near-future translation of nanorobots into clinical oncology.

Challenges and Limitations

Although nanorobots have demonstrated remarkable potential in preclinical cancer models, several challenges hinder their transition into routine clinical practice. One of the foremost obstacles is scalable and reproducible fabrication. Current methods allow for laboratory-scale synthesis of nanorobots with precise structural features; however, large-scale production with consistent quality remains difficult. Factors such as uniform size, surface chemistry, and functionalization must be standardized before clinical application [77]. Another major challenge is biocompatibility and long-term safety. While DNA origami, polymeric, and biomimetic nanorobots are generally considered safe, many designs rely on metallic components (e.g., gold, iron oxide, or titanium) that may accumulate in the liver, kidneys, or spleen and cause toxicity [78]. Additionally, nanorobots can be recognized by the immune system, leading to opsonization and clearance by macrophages, which reduces their circulation time and therapeutic efficacy [79]. Strategies such as cell-membrane coating or PEGylation have been explored to improve immune evasion, but these approaches are not foolproof. The navigation and control of nanorobots inside the human body presents another hurdle. While magnetic fields, ultrasound, or chemical gradients have been used successfully in small animals, achieving precise navigation in humans, especially in deep-seated tumors, remains technically demanding [80]. The complexity of the tumor microenvironment (TME) also adds difficulty. Features such as hypoxia, high interstitial fluid pressure, and dense extracellular matrix limit drug penetration and reduce the efficiency of nanorobot-based therapies [81]. In addition to biological and technical barriers, regulatory and ethical challenges must be addressed. Unlike traditional drugs, nanorobots integrate mechanical, biological, and computational functions, which complicates the regulatory framework. Agencies such as the FDA and EMA have yet to establish clear approval pathways for nanorobotic therapies [82]. Ethical considerations also arise regarding autonomous nanosystems operating within the human body, including issues of patient safety, long-term monitoring, and potential misuse. Finally, economic feasibility remains a limitation. The cost of producing sophisticated nanorobots with navigation and sensing capabilities is currently much higher than conventional nanoparticle-based systems. Without cost-effective manufacturing strategies, widespread clinical adoption will be difficult. Collectively, these challenges emphasize the need for interdisciplinary collaboration among nanotechnologists, oncologists, bioengineers, and regulatory experts to refine nanorobot design, ensure patient safety, and accelerate clinical translation.