Cancer is the 3rd leading cause of death globally, and the countries with low-to-middle income account for most cancer cases. The current diagnostic tools, including imaging, molecular detection, and immune histochemistry (IHC), have intrinsic limitations, such as poor accuracy. However, researchers have been working to improve anti-cancer treatment using different drug delivery systems (DDS) to target tumor cells more precisely. Current advances, however, are enough to meet the growing call for more efficient drug delivery systems, but the adverse effects of these systems are a major problem. Nanorobots are typically controlled devices made up of nanometric component assemblies that can interact with and even diffuse the cellular membrane due to their small size, offering a direct channel to the cellular level. The nanorobots improve treatment efficiency by performing advanced biomedical therapies using minimally invasive operations. Chemotherapy’s harsh side effects and untargeted drug distribution necessitate new cancer treatment trials. The nanorobots are currently designed to recognize 12 different types of cancer cells. Nanorobots are an emerging field of nanotechnology with nanoscale dimensions and are predictable to work at an atomic, molecular, and cellular level. Nanorobots to date are under the line of investigation, but some primary molecular models of these medically programmable machines have been tested. This review on nanorobots presents the various aspects allied, i.e., introduction, history, ideal characteristics, approaches in nanorobots, basis for the development, tool kit recognition and retrieval from the body, and application considering diagnosis and treatment.

1. WHO. Cancer. Available online: https://www.who.int/news-room/fact-sheets/detail/cancer (accessed on 3 February 2022).

2. Thun MJ, De Lancey JO, Center MM, et al. The global burden of cancer: Priorities for prevention. Carcinogenesis. 2010; 31(1): 100-110. doi: 10.1093/carcin/bgp263

3. Bray F, Møller B. Predicting the future burden of cancer. Nature Reviews Cancer. 2006; 6(1): 63-74. doi: 10.1038/nrc1781

4. Blackadar CB. Historical review of the causes of cancer. World Journal of Clinical Oncology. 2016; 7(1): 54-86. doi: 10.5306/wjco.v7.i1.54

5. GIZMODO, Egyptian mummy had prostate cancer; lots more ancient peeps probably did too. Available online: https://gizmodo.com/egyptian-mummy-had-prostate-cancerlots-more-ancient-p-5854019 (accessed on 3 February 2022).

6. N.C. Institute, Risk factors for cancer. Available online: https://www.cancer.gov/about-cancer/causes-prevention/risk (accessed on 3 February 2022).

7. Liu M, Yu X, Chen Z, et al. Aptamer selection and applications for breast cancer diagnostics and therapy. Journal of Nanobiotechnology. 2017; 15(1): 1-16. doi: 10.1186/s12951-017-0311-4

8. Chen T, Ren L, Liu X, et al. DNA nanotechnology for cancer diagnosis and therapy. International Journal of Nanomedicine. 2018; 19(6): 1671. doi: 10.3390/ijms19061671

9. Aeran H, Kumar V, Uniyal S, Tanwer P, et al. Nanodentistry: Is just a fiction or future. Journal of Oral Biology and Craniofacial Research. 2015; 5(3): 207-211. doi: 10.1016/j.jobcr.2015.06.012

10. Sarath KS, Nasim BP, Abraham E. Nanorobots a future device for diagnosis and treatment. Journal of Pharmacy and Pharmaceutics. 2018; 5(1): 44-49. doi: 10.15436/2377-1313.18.1815

11. Neto AMJC, Lopes IA, Pirota KR. A review on nanorobots. Journal of Computational and Theoretical Nanoscience. 2010; 7(10): 1870-1877. doi: 10.1166/jctn.2010.1552

12. Sivasankar M, Durairaj RB. Brief review on nano robots in bio medical applications. Advances in Robotics & Automation. 2012; 1(1): 101. doi: 10.4172/2168-9695.1000101

13. Manjunath V, Kishore V. The promising future in medicine: Nanorobots. Biomedical Science and Engineering. 2014; 2(2): 42-47. doi: 10.12691/bse-2-2-3

14. Jeong Y, Jin S, Palanikumar L, et al. Stimuli-responsive adaptive nanotoxin to directly penetrate the cellular membrane by molecular folding and unfolding. Journal of the American Chemical Society. 2022; 144(12): 5503-5516. doi: 10.1021/jacs.2c00084

15. Desrosiers A, Derbali RM, Hassine S, et al. Programmable self-regulated molecular buffers for precise sustained drug delivery. Nature Communications. 2022; 13(1): 1-13. doi: 10.1038/s41467-022-33491-7

16. Harroun SG, Prévost-Tremblay C, Lauzon D, et al. Programmable DNA switches and their applications. Nanoscale. 2018; 10: 4607-4641. doi: 10.1039/C7NR07348H

17. Lenaghan SC, Wang Y, Xi N, et al. Grand challenges in bioengineered nanorobots for cancer therapy. IEEE Transactions on Bio-Medical Engineering. 2013; 60(3): 667-673. doi: 10.1109/TBME.2013.2244599

18. Paul S. A brief insight into nanorobots. In: Bhattacharyya S, Das N, Bhattacharjee D (editors). Handbook of Research on Recent Developments in Intelligent Communication Application. IGI Global; 2017. pp. 23-74.

19. Ricotti L, Cafarelli A, Iacovacci V, et al. Advanced micro-nano-bio systems for future targeted therapies. Current Nanoscience. 2015; 11(2): 144-160. doi: 10.2174/1573413710666141114221246

20. Giri G, Maddahi Y, Zareinia K. A brief review on challenges in design and development of nanorobots for medical applications. Applied Sciences. 2021; 11(21): 10385. doi: 10.3390/app112110385

21. Vartholomeos P, Fruchard M, Ferreira A, Mavroidis C. MRI-Guided nanorobotic systems for therapeutic and diagnostic applications. Annual Review of Biomedical Engineering. 2011; 13: 157-184. doi: 10.1146/annurev-bioeng-071910-124724

22. Ungaro F, d’Angelo I, Miro A, et al. Engineered PLGA nano-and micro- carriers for pulmonary delivery: Challenges and promises. The Journal of Pharmacy and Pharmacology. 2012; 64(9): 1217-1235. doi: 10.1111/j.2042-7158.2012.01486.x

23. Pappu P, Madduru D, Chandrasekharan M, et al. Next generation sequencing analysis of lung cancer datasets: A functional genomics perspective. Indian Journal of Cancer. 2016; 53(1): 1-8. doi: 10.4103/0019-509X.180832

24. Verma SK, Chauhan R. Nanorobots in dentistry—A review. Indian Journal of Dentistry. 2014; 5: 62-70. doi: 10.1016/j.ijd.2012.12.010

25. Dixon KL. The radiation biology of radioimmunotherapy. Nuclear Medicine Communications. 2003; 24(9): 951-957. doi: 10.1097/00006231-200309000-00002

26. Reza KH, Asiwarya G, Radhika G, Bardalai D. Nanorobots: The future trend of drug delivery and therapeutics. International Journal of Pharmaceutical Sciences Review and Research. 2011; 10(1): 60-68.

27. Freitas RA. Medical nanorobots: The long-term goal for nanomedicine. Available online: http://www.nanomedicine.com/Papers/ArtechChapter2009.pdf (accessed on 3 February 2022).

28. Freitas RA. Pharmacytes: An ideal vehicle for targeted drug delivery. Journal of Nanoscience and Nanotechnology. 2006; 6(9-10): 2769-2775. doi: 10.1166/jnn.2006.413

29. Manjunath A, Kishore V. The promising future in medicine: Nanorobots. Biomedical Science and Engineering. 2014; 2(2): 42-47. doi: 10.12691/bse-2-2-3

30. Karan S, Banerjee B, Tripathi A, Majumder DD. Nanorobots control systems design—A new paradigm for healthcare system. In: Satapathy SC, Govardhan A, Raju KS, Mandal JK (editors). Emerging ICT for Bridging the Future, Proceedings of the 49th Annual Convention of the Computer Society of India (CSI); 12-14 December 2014; Hyderabad, Telangana, India. Springer; 2014. Volume 1.

31. Bhowmik D, Bhattacharjee C, Jayakar B. Role of nanotechnology in novel drug delivery system. Journal of Pharmaceutical Science and Technology. 2009; 1(1): 20-35.

32. Freitas RB. IMM report number 18: Nanomedicine. Clottocytes: Artificial mechanical platelets. Available online: http://www.imm.org/reports/rep018/ (accessed on 3 February 2022).

33. Dabbs DJ, Thompson LDR. Diagnostic Immunohistochemistry: Theranostic and Genomic Applications, 4th ed. Saunders; 2013.

34. Web of science. Available online: http://apps.webofknowledge.com/UA_GeneralSearch_input.do?product=UA&search_mode=GeneralSearch&SID=3DCzfvN7XkKHGA5i9Hu&preferencesSaved (accessed on 3 February 2022).

35. Golan DE, Tashjian AH, Armstrong EJ. Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 3rd ed. Lippincott Williams & Wilkins; 2011.

36. Ritter JM, Rang HP, Flower R, Henderson G. Rang & Dale’s Pharmacology, 8th ed. Churchill Livingstone; 2015.

37. National Health Surveillance Agency—An visa (Portuguese). Available online: http://portal.anvisa.gov.br/wps/content/anvisa+portal/anvisa/sala+de+imprensa/menu+-+noticias+anos/2015/publicadas+novas+normas+para+pesquisa+clinica (accessed on 3 February 2022).

38. Kratz F, Warnecke A. Finding the optimal balance: Challenges of improving conventional cancer chemotherapy using suitable combinations with nano-sized drug delivery systems. Journal of Controlled Release. 2012; 164(2): 221-235. doi: 10.1016/j.jconrel.2012.05.045

39. Zeeshan MA, Pané S, Youn SK, et al. Graphite coating of iron nanowires for nanorobotic applications: Synthesis, characterization and magnetic wireless manipulation. Advanced Functional Materials. 2012; 23(7): 823-831. doi: 10.1002/adfm.201202046

40. Kojima C, Suehiro T, Watanabe K, et al. Doxorubicin-conjugated dendrimer/collagen hybrid gels for metastasis-associated drug delivery systems. Acta Biomaterialia. 2013; 9(3): 5673-5780. doi: 10.1016/j.actbio.2012.11.013

41. Scialabba C, Licciardi M, Mauro N, et al. Inulin-based polymer coated SPIONs as potential drug delivery systems for targeted cancer therapy. European Journal of Pharmaceutics and Biopharmaceutics. 2014; 88(3): 695-705. doi: 10.1016/j.ejpb.2014.09.008

42. Watanabe K, Nishio Y, Makiura R, et al. Paclitaxel-loaded hydroxyapatite/collagen hybrid gels as drug delivery systems for metastatic cancer cells. International Journal of Pharmaceutics. 2013; 446(1-2): 81-86. doi: 10.1016/j.ijpharm.2013.02.002

43. Liu Z, Robinson JT, Tabakman SM, et al. Carbon materials for drug delivery & cancer therapy. Materials Today. 2011; 14(7-8): 316-323. doi: 10.1016/S1369-7021(11)70161-4

44. Health Quality Ontario. Intrathecal drug delivery systems for cancer pain: A health technology assessment. Ontario Health Technology Assessment Series. 2016; 16(1): 1-51.

45. Sutradhar KB, Amin L. Nanotechnology in cancer drug delivery and selective targeting. International Scholarly Research Notices. 2014; 2014: 939378. doi: 10.1155/2014/939378

46. Zhao G, Rodriguez BL. Molecular targeting of liposomal nanoparticles to tumor microenvironment. International Journal of Nanomedicine. 2013; 8: 61-71. doi: 10.2147/IJN.S37859

47. Coates A, Abraham S, Kaye SB, et al. On the receiving end-patient perception of the side-effects of cancer chemotherapy. European Journal of Cancer& Clinical Oncology. 1983; 19(2): 203-308. doi: 10.1016/0277-5379(83)90418-2

48. Tannock IF, Lee CM, Tunggal JK, et al. Limited penetration of anticancer drugs through tumor tissue: A potential cause of resistance of solid tumors to chemotherapy. Clinical Cancer Research. 2002; 8(3): 878-884.

49. Mousa SA, Bharali DJ. Nanotechnology-based detection and targeted therapy in cancer: Nano-bio paradigms and applications. Cancers. 2011; 3(3): 2888-2903. doi: 10.3390/cancers3032888

50. Links M, Brown R. Clinical relevance of the molecular mechanisms of resistance to anti-cancer drugs. Expert Reviews in Molecular Medicine. 1999; 1(15):1-21. doi: 10.1017/S1462399499001099X

51. World Health Organization. Cancer. Available online: http://www.who.int/cancer/en/ (accessed on 3 February 2022).

52. Mutoh K, Tsukahara S, Mitsuhashi J, et al. Estrogen-mediated post transcriptional down-regulation of P-glycoprotein in MDR1-transduced human breast cancer cells. Cancer Science. 2006; 97(11): 1198-1204. doi: 10.1111/j.1349-7006.2006.00300.x

53. Lagzi I. Chemical robotics—Chemotactic drug carriers. Central European Journal of Medicine. 2013; 8(4): 377-382. doi: 10.2478/s11536-012-0130-9

54. Xu X, Kim K, Fan D. Tunable release of multiplex biochemicals by plasmonically active rotary nanomotors. Angewandte Chemie (International Edition). 2015; 54(8): 2525-2529. doi: 10.1002/anie.201410754

55. Couvreur P, Gref R, Andrieux K, Malvy C. Nanotechnologies for drug delivery: Application to cancer and autoimmune diseases. Progress in Solid State Chemistry. 2006; 34(2-4): 231-235. doi: 10.1016/j.progsolidstchem.2005.11.009

56. Janda E, Nevolo M, Lehmann K, et al. Raf plus TGFβ-dependent EMT is initiated by endocytosis and lysosomal degradation of E-cadherin. Oncogene. 2006; 25(54): 7117-7130. doi: 10.1038/sj.onc.1209701

57. Osterlind K. Chemotherapy in small cell lung cancer. European Respiratory Journal. 2001; 18(6): 1026-1043. doi: 10.1183/09031936.01.00266101

58. Artemov D, Solaiyappan M, Bhujwalla ZM. Magnetic resonance pharmacoangiography to detect and predict chemotherapy delivery to solid tumors. Cancer Research. 2001; 61(7): 3039-3044.

59. Cavalcanti A, Shirinzadeh B, Freitas RA, Hogg T. Nanorobot architecture for medical target identification. Nanotechnology. 2007; 19(1): 015103. doi: 10.1088/0957-4484/19/01/015103

60. Sharma NN, Mittal RK. Nanorobot movement: Challenges and biologically inspired solutions. International Journal on Smart Sensing and Intelligent Systems2008; 1(1): 87-109. doi: 10.21307/ijssis-2017-280

61. Wang W, Li S, Mair L, et al. Acoustic propulsion of nanorod motors inside living cells. Angewandte Chemie (International Edition). 2014; 53(12): 3201-3204. doi: 10.1002/anie.201309629

62. Gao W, Dong R, Thamphiwatana S, et al. Artificial micromotors in the mouse’s stomach: A step toward in vivo use of synthetic motors. ACS Nano. 2015; 9(1): 117-123. doi: 10.1021/nn507097k

63. Juul S, Iacovelli F, Falconi M, et al. Temperature-controlled encapsulation and release of an active enzyme in the cavity of a self-assembled DNA nanocage. ACS Nano. 2013; 7(11): 9724-9734. doi: 10.1021/nn4030543

64. Ahmad A, Kamal A, Ashraf F, Ansari AF. A review on current scenario in the field of nanorobotics. International Journal of Engineering Sciences & Research Technology (IJESRT). 2014; 3(6): 578-584.

65. Fisher B. Biological research in the evolution of cancer surgery: A personal perspective. Cancer Research. 2008; 68(24): 10007-10020. doi: 10.1158/0008-5472

66. Cavalcanti A, Shirinzadeh B, Zhang M, Kretly LC. Nanorobot hardware architecture for medical defense. Sensors. 2008; 8(5): 2932-2958. doi: 10.3390/s8052932

67. Wong PC, Wong K, Foote H. Organic data memory using the DNA approach. Communications of the ACM. 2003; 46(1): 95-98. doi: 10.1145/602421.602426

68. Seeman NC. From genes to machines: DNA nanomechanical devices. Trends in Biochemical Sciences. 2005; 30(3): 119-125. doi: 10.1016/j.tibs.2005.01.007

69. Drexler KE. Nanosystems: Molecular Machinery, Manufacturing, and Computation, 1st ed. Wiley; 1992.

70. Hogg T, Kuekes PJ. Mobile microscopic sensors for high resolution in vivo diagnostics. Nanomedicine: Nanotechnology, Biology, and Medicine. 2006; 2(4): 239-247. doi: 10.1016/j.nano.2006.10.004

71. Bogaerts W, Baets R, Dumon P, et al. Nanophotonic waveguides in silicon-on-insulator fabricated with CMOS technology. Journal of Lightwave Technology. 2005; 23(1): 401-412. doi: 10.1109/JLT.2004.834471

72. Kubista PB. Creating Standard VHDL Test Environments. U.S. Patent 6,813,751, 2 November 2004.

73. Curtis ASG, Dalby M, Gadegaard N. Cell signaling arising from nanotopography: Implications for nanomedical devices. Nanomedicine. 2006; 1(1): 67-72. doi: 10.2217/17435889.1.1.67

74. Ahuja SP, Myers JR. A survey on wireless grid computing. Journal of Supercomputing. 2006; 37(1): 3-21. doi:10.1007/s11227-006-3845-z

75. Hanada E, Antoku Y, Tani S, et al. Electromagnetic interference on medical equipment by low-power mobile telecommunication systems. IEEE Transactions on Electromagnetic Compatibility. 2000; 42(4): 470-476. doi: 10.1109/15.902316

76. Sauer C, Stanacevic M, Cauwenberghs G, Thakor N. Power harvesting and telemetry in CMOS for implanted devices. IEEE Transactions on Circuits and Systems I: Regular Papers. 2005; 52(12): 2605-2613. doi: 10.1109/TCSI.2005.858183

77. Bernstein K, Chuang CT, Joshi R, Puri R. Design and CAD challenges in sub-90nm CMOS technologies. In: Proceedings of the International Conference on Computer Aided Design (ICCAD 2003); 9-13 November 2003; San Jose, CA, USA. pp. 129-136.

78. Mohseni P, Najafi K. Wireless multichannel biopotential recording using an integrated FM telemetry circuit. In: Proceedings of the 26th Annual International Conference of the IEEE Engineering in Medicine and Biology Society; 1-5 September 2004; San Francisco, CA, USA.

79. Eggers T, Marscher C, Marschner U, et al. Advanced hybrid integrated low-power telemetric pressure monitoring system for biomedical application. In: Proceedings of the IEEE Thirteenth Annual International Conference on Micro Electro Mechanical Systems (MEMS 2000); 23-27 January 2000; Miyazaki, Japan. pp. 23-37.

80. Ricciardi L, Pitz I, AI-Sarawi S, et al. Investigation into the future of RFID in biomedical applications. In: Proceedings of the Microtechnologies for the New Millenium 2003; 19-21 May 2003; Maspalomas, Gran Canaria, Spain.

81. Cavalcanti B, Shirinzadeh B, Freitas RA, Kretly LC. Medical nanorobot architecture based on nanobioelectronics. Recent Patents on Nanotechnology. 2007; 1(1): 1-10. doi: 10.2174/187221007779814745

82. Hogg T. Coordinating microscopic robots in viscous fluids. Autonomous Agents and Multi-Agent Systems. 2007; 14(3): 271-305. doi: 10.1007/s10458-006-9004-3

83. Horiuchi TK, Etienne-Cummings R. A time-series novelty detection chip for sonar. International Journal of Robotics and Automation. 2004; 19: 171-177.

84. Hamad-Schifferli K, Schwartz JJ, Santos AT, et al. Remote electronic control of DNA hybridization through inductive coupling to an attached metal nanocrystal antenna. Nature. 2002; 415(6868): 152-155. doi: 10.1038/415152a

85. Cavalcanti A, Shirinzadeh B, Zhang M. Nanorobot hardware architecture for medical defense. Sensors. 2008; 8: 2932-2958. doi: 10.3390/s8052932

86. Kharwade M, Nijhawan M, Modani S. Nanorobots: A future medical device in diagnosis and treatment. Research Journal of Pharmaceutical, Biological and Chemical Sciences. 2013; 4(2): 1299-1307.

87. Venkatesan M, Jolad B. Nanorobots in cancer treatment. In: Proceedings of the International Conference on Emerging Trends in Robotics and Communication Technologies (INTERACT 2010); 3-5 November 2010; Chennai, India. pp. 258-264.

88. Cavalcanti A, Shirinzadeh B, Kretly LC. Medical nanorobotics for diabetes control. Nanomedicine: Nanotechnology, Biology and Medicine. 2008; 4(2): 127-138. doi: 10.1016/j.nano.2008.03.001

89. Freitas RA. Nanotechnology, nanomedicine and nanosurgery. International Journal of Surgery. 2005; 3(4): 243-246. doi: 10.1016/j.ijsu.2005.10.007

90. Diez‐Sampedro A, Wright EM, Hirayama BA. Residue 457 controls sugar binding in the Na+/glucose cotransporter*. Journal of Biological Chemistry. 2001; 276(52): 49188-49194. doi: 10.1074/jbc.M108286200

91. Patil M, Mehta DS, Guvva S. Future impact of nanotechnology on medicine and dentistry. Journal of Indian Society of Periodontology. 2008; 12(2): 34-40. doi: 10.4103/0972-124X.44088

92. Cavalcanti A, Rosen L, Kretly LC, et al. Nanorobotic challenges in biomedical applications, design and control. In: Proceedings of the 11th IEEE International Conference on Electronics, Circuits and Systems (ICECS 2004); 13-15 December 2004; Tel Aviv, Israel.

93. Freitas RA. Computational tasks in medical nanorobotics. In: Eshaghian-Wilner MM (editor). Bio-Inspired and Nanoscale Integrated Computing. Wiley; 2009

94. Gupta J. Nanotechnology applications in medicine and dentistry. Journal of Investigative and Clinical Dentistry. 2011; 2: 81-88. doi: 10.1111/j.2041-1626.2011.00046.x