STIMULI-RESPONSIVE DRUG DELIVERY SYSTEMS: EXTENSIVE OVERVIEW

Authors

  • JAGAN SUBRAMANIAN Department of Pharmaceutics, JSS College of Pharmacy, Ooty, Nilgiris, Tamil Nadu, India https://orcid.org/0000-0002-9561-2821
  • RUTAMBHARA PADHY Department of Pharmaceutics, JSS College of Pharmacy, Ooty, Nilgiris, Tamil Nadu, India https://orcid.org/0009-0005-1964-6607
  • JANA ARUN Department of Pharmaceutics, JSS College of Pharmacy, Ooty, Nilgiris, Tamil Nadu, India https://orcid.org/0000-0003-1892-0633
  • VIVEK REDDY MURTHANNAGARI Department of Pharmaceutics, JSS College of Pharmacy, Ooty, Nilgiris, Tamil Nadu, India https://orcid.org/0000-0002-9077-9657
  • GANESH GNK Department of Pharmaceutics, JSS College of Pharmacy, Ooty, Nilgiris, Tamil Nadu, India

DOI:

https://doi.org/10.22159/ijap.2025v17i5.54389

Keywords:

Stimuli-responsive drug delivery, Theranostics, Bioelectronic interfaces, AI-Designed system, Controlled release, pH-responsive, Temperature-responsive, Multi-stimuli responsive, Targeted drug delivery, Nanomedicine

Abstract

Drug delivery systems based on stimuli-responsive materials offer a modern scientific solution to physicians who need drug release triggered by biological signals or outside influences. This review analyzes the complete developments in stimulus-responsive drug delivery system (SRDDS) throughout a decade from 2013 to 2024 by exploring their fundamental components together with their responsive action systems and therapeutic implementations.

The review investigates how various stimuli, including temperature, light, ultrasound, magnetic/electric fields, and intracellular factors like pH change, redox mechanisms, enzymes, glucose levels, inflammation, and hypoxia, influence responsive systems that have the ability to respond to several stimuli. An assessment of delivery system materials takes place, including smart hydrogels, inorganic nanoparticles, biomimetic constructs, and smart polymers, along with their respective release strategies.

Research outcomes from clinics imply important therapeutic benefits of responsive system for different diseases because patients receiving cancer treatment experienced 37% greater tumor response rates, while diabetes patients showed 42% fewer hypoglycemic events, and inflammatory bowel disease (IBD) patients achieved 52% better endoscopic remission results. The remarkable achievements in delivery system have been accompanied by persistent obstacles related to large-scale manufacturing, biological challenges, and translation into clinical practice. This development now incorporates three major forward directions that unite artificial intelligence (AI) designed systems with bioelectronic interfaces and biosensors used in closed-loop frameworks.

The analysis shows how responsive pharmaceutical delivery systems can solve pharmaceutical issues, yet needed collaborative efforts from multiple disciplines will drive their complete medical utilization.

References

1. Zhang Y, Huang Y, Li S. Polymeric micelles: nanocarriers for cancer-targeted drug delivery. AAPS PharmSciTech. 2014 Aug;15(4):862-71. doi: 10.1208/s12249-014-0113-z, PMID 24700296.

2. Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat Mater. 2013 Nov;12(11):991-1003. doi: 10.1038/nmat3776, PMID 24150417.

3. Karimi M, Ghasemi A, Sahandi Zangabad P, Rahighi R, Moosavi Basri SM, Mirshekari H. Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems. Chem Soc Rev. 2016 Mar 7;45(5):1457-501. doi: 10.1039/c5cs00798d, PMID 26776487, PMCID PMC4775468.

4. Agrawal SS, Baliga V, Londhe VY. Liposomal formulations: a recent update. Pharmaceutics. 2024 Dec 30;17(1):36. doi: 10.3390/pharmaceutics17010036, PMID 39861685, PMCID PMC11769406.

5. Wang J, Zhang Y, Aghda NH, Pillai AR, Thakkar R, Nokhodchi A. Emerging 3D printing technologies for drug delivery devices: current status and future perspective. Adv Drug Deliv Rev. 2021 Jul;174:294-316. doi: 10.1016/j.addr.2021.04.019, PMID 33895212.

6. Lin M, Qi X. Advances and challenges of stimuli responsive nucleic acids delivery system in gene therapy. Pharmaceutics. 2023 May 10;15(5):1450. doi: 10.3390/pharmaceutics15051450, PMID 37242692, PMCID PMC10220631.

7. Xie B, Xie H. Application of stimuli responsive hydrogel in brain disease treatment. Front Bioeng Biotechnol. 2024 Jul 18;12:1450267. doi: 10.3389/fbioe.2024.1450267, PMID 39091971, PMCID PMC11291207.

8. Mitragotri S. Devices for overcoming biological barriers: the use of physical forces to disrupt the barriers. Adv Drug Deliv Rev. 2013 Jan;65(1):100-3. doi: 10.1016/j.addr.2012.07.016, PMID 22960787.

9. Cheng YH, He C, Riviere JE, Monteiro Riviere NA, Lin Z. Meta-analysis of nanoparticle delivery to tumors using a physiologically based pharmacokinetic modeling and simulation approach. ACS Nano. 2020 Mar 24;14(3):3075-95. doi: 10.1021/acsnano.9b08142, PMID 32078303, PMCID PMC7098057.

10. Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress challenges and opportunities. Nat Rev Cancer. 2017 Jan;17(1):20-37. doi: 10.1038/nrc.2016.108, PMID 27834398, PMCID PMC5575742.

11. Guo Q, Qiu X, Zhang X. Recent advances in electronic skins with multiple-stimuli responsive and self-healing abilities. Materials (Basel). 2022 Feb 23;15(5):1661. doi: 10.3390/ma15051661, PMID 35268894, PMCID PMC8911295.

12. Nie T, Wang W, Liu X, Wang Y, Li K, Song X. Sustained release systems for delivery of therapeutic peptide/protein. Biomacromolecules. 2021 Jun 14;22(6):2299-324. doi: 10.1021/acs.biomac.1c00160, PMID 33957752.

13. Kopecek J. Polymer drug conjugates: origins progress to date and future directions. Adv Drug Deliv Rev. 2013 Jan;65(1):49-59. doi: 10.1016/j.addr.2012.10.014, PMID 23123294, PMCID PMC3565043.

14. Kamaly N, Yameen B, Wu J, Farokhzad OC. Degradable controlled release polymers and polymeric nanoparticles: mechanisms of controlling drug release. Chem Rev. 2016 Feb 24;116(4):2602-63. doi: 10.1021/acs.chemrev.5b00346, PMID 26854975, PMCID PMC5509216.

15. Ulbrich K, Hola K, Subr V, Bakandritsos A, Tucek J, Zboril R. Targeted drug delivery with polymers and magnetic nanoparticles: covalent and noncovalent approaches, release control and clinical studies. Chem Rev. 2016 May 11;116(9):5338-431. doi: 10.1021/acs.chemrev.5b00589, PMID 27109701.

16. Bedard MF, De Geest BG, Skirtach AG, Mohwald H, Sukhorukov GB. Polymeric microcapsules with light-responsive properties for encapsulation and release. Adv Colloid Interface Sci. 2010 Jul 12;158(1-2):2-14. doi: 10.1016/j.cis.2009.07.007, PMID 19720369.

17. Lin CC, Anseth KS. PEG hydrogels for the controlled release of biomolecules in regenerative medicine. Pharm Res. 2009 Mar;26(3):631-43. doi: 10.1007/s11095-008-9801-2, PMID 19089601, PMCID PMC5892412.

18. Ju Y, Liao H, Richardson JJ, Guo J, Caruso F. Nanostructured particles assembled from natural building blocks for advanced therapies. Chem Soc Rev. 2022;51(11):4287-336. doi: 10.1039/D1CS00343G, PMID 35471996.

19. Zhang YS, Khademhosseini A. Advances in engineering hydrogels. Science. 2017 May 5;356(6337):eaaf3627. doi: 10.1126/science.aaf3627, PMID 28473537, PMCID PMC5841082.

20. Fatima M, Almalki WH, Khan T, Sahebkar A, Kesharwani P. Harnessing the power of stimuli-responsive nanoparticles as an effective therapeutic drug delivery system. Adv Mater. 2024 Jun;36(24):e2312939. doi: 10.1002/adma.202312939, PMID 38447161.

21. Liu M, Du H, Zhang W, Zhai G. Internal stimuli-responsive nanocarriers for drug delivery: design strategies and applications. Mater Sci Eng C Mater Biol Appl. 2017 Feb 1;71:1267-80. doi: 10.1016/j.msec.2016.11.030, PMID 27987683.

22. Grimm O, Wendler F, Schacher FH. Micellization of photo-responsive block copolymers. Polymers (Basel). 2017 Aug 26;9(9):396. doi: 10.3390/polym9090396, PMID 30965699, PMCID PMC6418654.

23. Linsley CS, Wu BM. Recent advances in light responsive on demand drug delivery systems. Ther Deliv. 2017 Feb;8(2):89-107. doi: 10.4155/tde-2016-0060, PMID 28088880, PMCID PMC5561969.

24. Sirsi S, Borden M. Microbubble compositions properties and biomedical applications. Bubble Sci Eng Technol. 2009 Nov;1(1-2):3-17. doi: 10.1179/175889709X446507, PMID 20574549, PMCID PMC2889676.

25. Kumar CS, Mohammad F. Magnetic nanomaterials for hyperthermia based therapy and controlled drug delivery. Adv Drug Deliv Rev. 2011 Aug 14;63(9):789-808. doi: 10.1016/j.addr.2011.03.008, PMID 21447363, PMCID PMC3138885.

26. Ge J, Neofytou E, Cahill TJ, Beygui RE, Zare RN. Drug release from electric field responsive nanoparticles. ACS Nano. 2012 Jan 24;6(1):227-33. doi: 10.1021/nn203430m, PMID 22111891, PMCID PMC3489921.

27. Pillay V, Tsai TS, Choonara YE, du Toit LC, Kumar P, Modi G. A review of integrating electroactive polymers as responsive systems for specialized drug delivery applications. J Biomed Mater Res A. 2014 Jun;102(6):2039-54. doi: 10.1002/jbm.a.34869, PMID 23852673.

28. Hoffman AS. Stimuli responsive polymers: biomedical applications and challenges for clinical translation. Adv Drug Deliv Rev. 2013 Jan;65(1):10-6. doi: 10.1016/j.addr.2012.11.004, PMID 23246762.

29. Ma P, Lai X, Luo Z, Chen Y, Loh XJ, Ye E. Recent advances in mechanical force-responsive drug delivery systems. Nanoscale Adv. 2022 Jul 18;4(17):3462-78. doi: 10.1039/d2na00420h, PMID 36134346, PMCID PMC9400598.

30. Patra JK, Das G, Fraceto LF, Campos EV, Rodriguez Torres MD, Acosta Torres LS. Nano based drug delivery systems: recent developments and future prospects. J Nanobiotechnology. 2018 Sep 19;16(1):71. doi: 10.1186/s12951-018-0392-8, PMID 30231877, PMCID PMC6145203.

31. Guan J, Zhou ZQ, Chen MH, Li HY, Tong DN, Yang J. Folate conjugated and pH-responsive polymeric micelles for target cell specific anticancer drug delivery. Acta Biomater. 2017 Sep 15;60:244-55. doi: 10.1016/j.actbio.2017.07.018, PMID 28713015.

32. Yang Y, Sun W. Recent advances in redox responsive nanoparticles for combined cancer therapy. Nanoscale Adv. 2022 Jul 28;4(17):3504-16. doi: 10.1039/d2na00222a, PMID 36134355, PMCID PMC9400520.

33. Dhandapani TS, Krishnan V, Muthukumar B, Elango V, Lakshmanan SS, Sam Jenkinson SH. Emerging trends in stimuli sensitive drug delivery system: a comprehensive review of clinical applications and recent advancements. Int J App Pharm. 2023;15(6):38-44. doi: 10.22159/ijap.2023v15i6.48974.

34. Wang J, Wang Z, Yu J, Kahkoska AR, Buse JB, Gu Z. Glucose responsive insulin and delivery systems: innovation and translation. Adv Mater. 2020 Apr;32(13):e1902004. doi: 10.1002/adma.201902004, PMID 31423670, PMCID PMC7141789.

35. Tian J, Chen T, Huang B, Liu Y, Wang C, Cui Z. Inflammation specific environment activated methotrexate loaded nanomedicine to treat rheumatoid arthritis by immune environment reconstruction. Acta Biomater. 2023 Feb;157:367-80. doi: 10.1016/j.actbio.2022.12.007, PMID 36513249.

36. Zhou M, Xie Y, Xu S, Xin J, Wang J, Han T. Hypoxia activated nanomedicines for effective cancer therapy. Eur J Med Chem. 2020 Jun 1;195:112274. doi: 10.1016/j.ejmech.2020.112274, PMID 32259703.

37. Luo Y, Yin X, Yin X, Chen A, Zhao L, Zhang G. Dual pH/redox responsive mixed polymeric micelles for anticancer drug delivery and controlled release. Pharmaceutics. 2019 Apr 11;11(4):176. doi: 10.3390/pharmaceutics11040176, PMID 30978912, PMCID PMC6523239.

38. Zhou J, Yang R, Chen Y, Chen D. Efficacy tumor therapeutic applications of stimuli-responsive block copolymer based nano-assemblies. Heliyon. 2024 Mar 19;10(7):e28166. doi: 10.1016/j.heliyon.2024.e28166, PMID 38571609, PMCID PMC10987934.

39. He Y, Cong C, Li X, Zhu R, Li A, Zhao S. Nano-drug system based on hierarchical drug release for deep localized/systematic cascade tumor therapy stimulating antitumor immune responses. Theranostics. 2019 May 4;9(10):2897-909. doi: 10.7150/thno.33534, PMID 31244931, PMCID PMC6568183.

40. Xia Y, Duan S, Han C, Jing C, Xiao Z, Li C. Hypoxia-responsive nanomaterials for tumor imaging and therapy. Front Oncol. 2022 Dec 15;12:1089446. doi: 10.3389/fonc.2022.1089446, PMID 36591450, PMCID PMC9798000.

41. Bordbar Khiabani A, Gasik M. Smart hydrogels for advanced drug delivery systems. Int J Mol Sci. 2022 Mar 27;23(7):3665. doi: 10.3390/ijms23073665, PMID 35409025, PMCID PMC8998863.

42. Yadav NK, Mazumder R, Rani A, Kumar A. Current perspectives on using nanoparticles for diabetes management. Int J App Pharm. 2024;16(5):38-45. doi: 10.22159/ijap.2024v16i5.51084.

43. Madaan K, Kumar S, Poonia N, Lather V, Pandita D. Dendrimers in drug delivery and targeting: drug dendrimer interactions and toxicity issues. J Pharm Bioallied Sci. 2014 Jul;6(3):139-50. doi: 10.4103/0975-7406.130965, PMID 25035633, PMCID PMC4097927.

44. Cabral H, Kataoka K. Progress of drug loaded polymeric micelles into clinical studies. J Control Release. 2014 Sep 28;190:465-76. doi: 10.1016/j.jconrel.2014.06.042, PMID 24993430.

45. Guo X, Wei X, Jing Y, Zhou S. Size changeable nanocarriers with nuclear targeting for effectively overcoming multidrug resistance in cancer therapy. Adv Mater. 2015 Nov 4;27(41):6450-6. doi: 10.1002/adma.201502865, PMID 26401989.

46. Jiang T, Zhan Y, Ding J, Song Z, Zhang Y, Li J. Biomimetic cell membrane coated nanoparticles for cancer theranostics. ChemMedChem. 2024 Nov 18;19(22):e202400410. doi: 10.1002/cmdc.202400410, PMID 39264862.

47. Panja S, Dey G, Bharti R, Kumari K, Maiti TK, Mandal M. Tailor made temperature sensitive micelle for targeted and on demand release of anticancer drugs. ACS Appl Mater Interfaces. 2016 May 18;8(19):12063-74. doi: 10.1021/acsami.6b03820, PMID 27128684.

48. Cheng R, Feng F, Meng F, Deng C, Feijen J, Zhong Z. Glutathione responsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery. J Control Release. 2011 May 30;152(1):2-12. doi: 10.1016/j.jconrel.2011.01.030, PMID 21295087.

49. Zhou Q, Hou Y, Zhang L, Wang J, Qiao Y, Guo S. Dual-pH sensitive charge-reversal nanocomplex for tumor targeted drug delivery with enhanced anticancer activity. Theranostics. 2017 Apr 10;7(7):1806-19. doi: 10.7150/thno.18607, PMID 28638469, PMCID PMC5479270.

50. Dai Y, Su J, Wu K, Ma W, Wang B, Li M. Correction to multifunctional thermosensitive liposomes based on natural phase change material: near-infrared light triggered drug release and multimodal imaging guided cancer combination therapy. ACS Appl Mater Interfaces ACS Appl Mater Interfaces. 2024;16(46):64388. doi: 10.1021/acsami.4c17950, PMID 39514435.

51. Wu W, Zhou S. Responsive materials for self-regulated insulin delivery. Macromol Biosci. 2013 Nov;13(11):1464-77. doi: 10.1002/mabi.201300120, PMID 23839986.

52. Lee HP, Gaharwar AK. Light responsive inorganic biomaterials for biomedical applications. Adv Sci (Weinh). 2020 Jul 17;7(17):2000863. doi: 10.1002/advs.202000863, PMID 32995121, PMCID PMC7507067.

53. Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov. 2021 Feb;20(2):101-24. doi: 10.1038/s41573-020-0090-8, PMID 33277608, PMCID PMC7717100.

54. Andronescu E, Ficai A, Albu MG, Mitran V, Sonmez M, Ficai D. Collagen hydroxyapatite/cisplatin drug delivery systems for locoregional treatment of bone cancer. Technol Cancer Res Treat. 2013 Aug;12(4):275-84. doi: 10.7785/tcrt.2012.500331, PMID 23547973.

55. Lee S, Tong X, Yang F. Effects of the poly(ethylene glycol) hydrogel crosslinking mechanism on protein release. Biomater Sci. 2016 Mar;4(3):405-11. doi: 10.1039/c5bm00256g, PMID 26539660, PMCID PMC5127629.

56. Zhang Y, Yu J, Ren K, Zuo J, Ding J, Chen X. Thermosensitive hydrogels as scaffolds for cartilage tissue engineering. Biomacromolecules. 2019 Apr 8;20(4):1478-92. doi: 10.1021/acs.biomac.9b00043, PMID 30843390.

57. Aldawood FK, Andar A, Desai S. A comprehensive review of microneedles: types materials processes, characterizations and applications. Polymers (Basel). 2021 Aug 22;13(16):2815. doi: 10.3390/polym13162815, PMID 34451353, PMCID PMC8400269.

58. Wang Y, Li H, Rasool A, Wang H, Manzoor R, Zhang G. Polymeric nanoparticles (PNPs) for oral delivery of insulin. J Nanobiotechnology. 2024 Jan 3;22(1):1. doi: 10.1186/s12951-023-02253-y, PMID 38167129, PMCID PMC10763344.

59. Zhang YB, Xu D, Bai L, Zhou YM, Zhang H, Cui YL. A review of non-invasive drug delivery through respiratory routes. Pharmaceutics. 2022 Sep 19;14(9):1974. doi: 10.3390/pharmaceutics14091974, PMID 36145722, PMCID PMC9506287.

60. Hoffman AS. Stimuli-responsive polymers: biomedical applications and challenges for clinical translation. Adv Drug Deliv Rev. 2013 Jan;65(1):10-6. doi: 10.1016/j.addr.2012.11.004, PMID 23246762.

61. Zhao L, Kim MJ, Zhang L, Lionberger R. Generating model integrated evidence for generic drug development and assessment. Clin Pharmacol Ther. 2019 Feb;105(2):338-49. doi: 10.1002/cpt.1282, PMID 30414386.

62. Marzaman AN, Roska TP, Sartini S, Utami RN, Sulistiawati S, Enggi CK. Recent advances in pharmaceutical approaches of antimicrobial agents for selective delivery in various administration routes. Antibiotics (Basel). 2023 Apr 27;12(5):822. doi: 10.3390/antibiotics12050822, PMID 37237725, PMCID PMC10215767.

63. Kofoed RH, Aubert I. Focused ultrasound gene delivery for the treatment of neurological disorders. Trends Mol Med. 2024 Mar;30(3):263-77. doi: 10.1016/j.molmed.2023.12.006, PMID 38216449.

64. Wang Y, Wu H, Zhou Z, Maitz MF, Liu K, Zhang B. A thrombin triggered self-regulating anticoagulant strategy combined with anti-inflammatory capacity for blood contacting implants. Sci Adv. 2022 Mar 4;8(9):eabm3378. doi: 10.1126/sciadv.abm3378, PMID 35245113, PMCID PMC8896797.

65. Pandey M, Choudhury H, Binti Abd Aziz A, Bhattamisra SK, Gorain B, Su JS. Potential of stimuli responsive in situ gel system for sustained ocular drug delivery: recent progress and contemporary research. Polymers (Basel). 2021 Apr 20;13(8):1340. doi: 10.3390/polym13081340, PMID 33923900, PMCID PMC8074213.

66. Lai HJ, Kuan CH, Wu HC, Tsai JC, Chen TM, Hsieh DJ. Tailored design of electrospun composite nanofibers with staged release of multiple angiogenic growth factors for chronic wound healing. Acta Biomater. 2014 Oct;10(10):4156-66. doi: 10.1016/j.actbio.2014.05.001, PMID 24814882.

67. Poole KM, Nelson CE, Joshi RV, Martin JR, Gupta MK, Haws SC. ROS-responsive microspheres for on demand antioxidant therapy in a model of diabetic peripheral arterial disease. Biomaterials. 2015 Feb;41:166-75. doi: 10.1016/j.biomaterials.2014.11.016, PMID 25522975, PMCID PMC4274772.

68. Sharma IS, Thakur MO, Singh SH, Tripathi AS. Microfluidic devices as a tool for drug delivery and diagnosis: a review. Int J App Pharm. 2021;13(1):95-102. doi: 10.22159/ijap.2021v13i1.39032.

69. Xuan Y, Guan M, Zhang S. Tumor immunotherapy and multi-mode therapies mediated by medical imaging of Nanoprobes. Theranostics. 2021 May 25;11(15):7360-78. doi: 10.7150/thno.58413, PMID 34158855, PMCID PMC8210602.

70. Peng X, Wang Y, Zhang J, Zhang Z, Qi S. Intravital imaging of the functions of immune cells in the tumor microenvironment during immunotherapy. Front Immunol. 2023 Dec 6;14:1288273. doi: 10.3389/fimmu.2023.1288273, PMID 38124754, PMCID PMC10730658.

71. Lapuk SE, Mukhametzyanov TA, Schick C, Gerasimov AV. Crystallization kinetics and glass forming ability of rapidly crystallizing drugs studied by fast scanning calorimetry. Int J Pharm. 2021 Apr 15;599:120427. doi: 10.1016/j.ijpharm.2021.120427, PMID 33662469.

72. Kumar D, Nadda R, Repaka R. Advances and challenges in organ on chip technology: toward mimicking human physiology and disease in vitro. Med Biol Eng Comput. 2024 Jul;62(7):1925-57. doi: 10.1007/s11517-024-03062-7, PMID 38436835.

73. Tahover E, Patil YP, Gabizon AA. Emerging delivery systems to reduce doxorubicin cardiotoxicity and improve therapeutic index: focus on liposomes. Anti-Cancer Drugs. 2015 Mar;26(3):241-58. doi: 10.1097/CAD.0000000000000182, PMID 25415656.

74. Steverink JG, Van Tol FR, Oosterman BJ, Vermonden T, Verlaan JJ, Malda J. Robust gelatin hydrogels for local sustained release of bupivacaine following spinal surgery. Acta Biomater. 2022 Jul 1;146:145-58. doi: 10.1016/j.actbio.2022.05.007, PMID 35562007.

75. Ning C, Guo Y, Yan L, Thawani JP, Zhang W, Fu C. On demand prolongation of peripheral nerve blockade through bupivacaine loaded hydrogels with suitable residence periods. ACS Biomater Sci Eng. 2019 Feb 11;5(2):696-709. doi: 10.1021/acsbiomaterials.8b01107, PMID 33405832.

76. Chou PY, Chen SH, Chen CH, Chen SH, Fong YT, Chen JP. Thermo responsive in-situ forming hydrogels as barriers to prevent post operative peritendinous adhesion. Acta Biomater. 2017 Nov;63:85-95. doi: 10.1016/j.actbio.2017.09.010, PMID 28919215.

77. Li H, He J, Zhang M, Liu J, Ni P. Glucose sensitive polyphosphoester diblock copolymer for an insulin delivery system. ACS Biomater Sci Eng. 2020 Mar 9;6(3):1553-64. doi: 10.1021/acsbiomaterials.9b01817, PMID 33455388.

78. Perkins BA, Sherr JL, Mathieu C. Type 1 diabetes glycemic management: insulin therapy glucose monitoring and automation. Science. 2021 Jul 30;373(6554):522-7. doi: 10.1126/science.abg4502, PMID 34326234.

79. Jarosinski MA, Dhayalan B, Rege N, Chatterjee D, Weiss MA. Smart insulin delivery technologies and intrinsic glucose responsive insulin analogues. Diabetologia. 2021 May;64(5):1016-29. doi: 10.1007/s00125-021-05422-6, PMID 33710398, PMCID PMC8158166.

80. Xie X, Wang Y, Deng B, Blatchley MR, Lan D, Xie Y. Matrix metalloproteinase responsive hydrogels with tunable retention for on-demand therapy of inflammatory bowel disease. Acta Biomater. 2024;186:354-68. doi: 10.1016/j.actbio.2024.07.054, PMID 39117116.

81. Lee SH, Bajracharya R, Min JY, Han JW, Park BJ, Han HK. Strategic approaches for colon targeted drug delivery: an overview of recent advancements. Pharmaceutics. 2020 Jan 15;12(1):68. doi: 10.3390/pharmaceutics12010068, PMID 31952340, PMCID PMC7022598.

82. Wong PT, Choi SK. Mechanisms of drug release in nanotherapeutic delivery systems. Chem Rev. 2015 May 13;115(9):3388-432. doi: 10.1021/cr5004634, PMID 25914945.

83. Yin X, Harmancey R, Frierson B, Wu JG, Moody MR, McPherson DD. Efficient gene editing for heart disease via ELIP-based CRISPR delivery system. Pharmaceutics. 2024 Feb 29;16(3):343. doi: 10.3390/pharmaceutics16030343, PMID 38543237, PMCID PMC10974117.

84. Rad IJ, Chapman L, Tupally KR, Veidt M, Al Sadiq H, Sullivan R. A systematic review of ultrasound mediated drug delivery to the eye and critical insights to facilitate a timely path to the clinic. Theranostics. 2023 Jun 19;13(11):3582-638. doi: 10.7150/thno.82884, PMID 37441595, PMCID PMC10334839.

85. Gorick CM, Chappell JC, Price RJ. Applications of ultrasound to stimulate therapeutic revascularization. Int J Mol Sci. 2019 Jun 24;20(12):3081. doi: 10.3390/ijms20123081, PMID 31238531, PMCID PMC6627741.

86. Ma Y, Song Y, Ma F, Chen G. A potential polymeric nanogel system for effective delivery of chlorogenic acid to target collagen induced arthritis. J Inorg Organomet Polym Mater. 2020 Jul;30(7):2356-65. doi: 10.1007/s10904-019-01421-8.

87. Qian C, Wang J, Qian Y, Hu R, Zou J, Zhu C. Tumor cell surface adherable peptide drug conjugate prodrug nanoparticles inhibit tumor metastasis and augment treatment efficacy. Nano Lett. 2020 Jun 10;20(6):4153-61. doi: 10.1021/acs.nanolett.0c00152, PMID 32462880.

88. Jaroszewski B, Jelonek K, Kasperczyk J. Drug delivery systems of betulin and its derivatives: an overview. Biomedicines. 2024 May 24;12(6):1168. doi: 10.3390/biomedicines12061168, PMID 38927375, PMCID PMC11200571.

89. Yang Y, Shao Q, Deng R, Wang C, Teng X, Cheng K. In vitro and in vivo uncaging and bioluminescence imaging by using photocaged upconversion nanoparticles. Angew Chem Int Ed Engl. 2012 Mar 26;51(13):3125-9. doi: 10.1002/anie.201107919, PMID 22241651.

90. Zhao N, Wu B, Hu X, Xing D. NIR-triggered high efficient photodynamic and chemo-cascade therapy using caspase-3 responsive functionalized upconversion nanoparticles. Biomaterials. 2017 Oct;141:40-9. doi: 10.1016/j.biomaterials.2017.06.031, PMID 28666101.

91. Wang S, Hou Y. New types of magnetic nanoparticles for stimuli responsive theranostic nanoplatforms. Adv Sci (Weinh). 2024 Feb;11(8):e2305459. doi: 10.1002/advs.202305459, PMID 37988692, PMCID PMC10885654.

92. Hyder F, Manjura Hoque S. Brain tumor diagnostics and therapeutics with superparamagnetic ferrite nanoparticles. Contrast Media Mol Imaging. 2017 Dec 11;2017:6387217. doi: 10.1155/2017/6387217, PMID 29375280, PMCID PMC5742516.

93. Sheervalilou R, Shirvaliloo M, Sargazi S, Ghaznavi H. Recent advances in iron oxide nanoparticles for brain cancer theranostics: from in vitro to clinical applications. Expert Opin Drug Deliv. 2021 Jul;18(7):949-77. doi: 10.1080/17425247.2021.1888926, PMID 33567919.

94. Mastall M, Roth P, Bink A, Fischer Maranta A, Laubli H, Hottinger AF. A phase Ib/II randomized open label drug repurposing trial of glutamate signaling inhibitors in combination with chemoradiotherapy in patients with newly diagnosed glioblastoma: the GLUGLIO trial protocol. BMC Cancer. 2024 Jan 15;24(1):82. doi: 10.1186/s12885-023-11797-z, PMID 38225589, PMCID PMC10789019.

95. Pan X, Chen J, Yang M, Wu J, He G, Yin Y. Enzyme/pH dual-responsive polymer prodrug nanoparticles based on 10-hydroxycamptothecin-carboxymethylchitosan for enhanced drug stability and anticancer efficacy. Eur Polym J. 2019 Aug 1;117:372-81. doi: 10.1016/j.eurpolymj.2019.04.050.

96. Bhattacharya S, Prajapati BG, Singh S. A critical review on the dissemination of PH and stimuli responsive polymeric nanoparticular systems to improve drug delivery in cancer therapy. Crit Rev Oncol Hematol. 2023 May;185:103961. doi: 10.1016/j.critrevonc.2023.103961, PMID 36921781.

97. Li H, Hao Z, Zhang S, Li B, Wang Y, Wu X. Smart stimuli responsive injectable gels for bone tissue engineering application. Macromol Biosci. 2023 Jun;23(6):e2200481. doi: 10.1002/mabi.202200481, PMID 36730643.

98. Watt FE. Posttraumatic osteoarthritis: what have we learned to advance osteoarthritis? Curr Opin Rheumatol. 2021 Jan;33(1):74-83. doi: 10.1097/BOR.0000000000000760, PMID 33186246.

99. Watt FE. Posttraumatic osteoarthritis: what have we learned to advance osteoarthritis? Curr Opin Rheumatol. 2021 Jan;33(1):74-83. doi: 10.1097/BOR.0000000000000760, PMID 33186246.

100. Di Ianni E, Jacobsen NR, Vogel U, Moller P. Predicting nanomaterials pulmonary toxicity in animals by cell culture models: achievements and perspectives. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022 Nov;14(6):e1794. doi: 10.1002/wnan.1794, PMID 36416018, PMCID PMC9786239.

101. Perugini V, Schmid R, Morch Y, Texier I, Brodde M, Santin M. A multistep in vitro hemocompatibility testing protocol recapitulating the foreign body reaction to nanocarriers. Drug Deliv Transl Res. 2022 Sep;12(9):2089-100. doi: 10.1007/s13346-022-01141-6, PMID 35318565, PMCID PMC9360154.

102. Souto EB, Blanco Llamero C, Krambeck K, Kiran NS, Yashaswini C, Postwala H. Regulatory insights into nanomedicine and gene vaccine innovation: safety assessment challenges and regulatory perspectives. Acta Biomater. 2024 May;180:1-17. doi: 10.1016/j.actbio.2024.04.010, PMID 38604468.

103. Taha MS, Padmakumar S, Singh A, Amiji MM. Critical quality attributes in the development of therapeutic nanomedicines toward clinical translation. Drug Deliv Transl Res. 2020 Jun;10(3):766-90. doi: 10.1007/s13346-020-00744-1, PMID 32170656.

104. Gao F, Yu B, Cong H, Shen Y. Delivery process and effective design of vectors for cancer therapy. J Mater Chem B. 2022;10(36):6896-921. doi: 10.1039/D2TB01326F, PMID 36048171.

105. Paliwal R, Kumar P, Chaurasiya A, Kenwat R, Katke S, Paliwal SR. Development of nanomedicines and nano-similars: recent advances in regulatory landscape. Curr Pharm Des. 2022;28(2):165-77. doi: 10.2174/1381612827666211115170001, PMID 34781869.

106. Singh AV, Chandrasekar V, Prabhu VM, Bhadra J, Laux P, Bhardwaj P. Sustainable bioinspired materials for regenerative medicine: balancing toxicology environmental impact and ethical considerations. Biomed Mater. 2024 Oct 18;19(6). doi: 10.1088/1748-605X/ad85bb, PMID 39389102.

107. Chen C, Yaari Z, Apfelbaum E, Grodzinski P, Shamay Y, Heller DA. Merging data curation and machine learning to improve nanomedicines. Adv Drug Deliv Rev. 2022 Apr;183:114172. doi: 10.1016/j.addr.2022.114172, PMID 35189266, PMCID PMC9233944.

108. Gholap AD, Uddin MJ, Faiyazuddin M, Omri A, Gowri S, Khalid M. Advances in artificial intelligence for drug delivery and development: a comprehensive review. Comput Biol Med. 2024 Aug;178:108702. doi: 10.1016/j.compbiomed.2024.108702, PMID 38878397.

109. Alshamrani AI, Al Hadi AY, Almutairi AH, ALkhweildy WS, Aldubiban GM, Moafa AM, Alshehri FA, Alnami MH, Alqarni AA, Ayoub ZH, Banajia MA. Advancing targeted drug delivery: the role of smart polymers in responsive therapeutic systems. Egyptian Journal of Chemistry. 2024 Dec 1;67(13):1549-56. doi: 10.21608/EJCHEM.2024.337880.10836.

110. Ma Q, Zhao X, Shi A, Wu J. Bioresponsive functional phenylboronic acid based delivery system as an emerging platform for diabetic therapy. Int J Nanomedicine. 2021 Jan 12;16:297-314. doi: 10.2147/IJN.S284357, PMID 33488074, PMCID PMC7816047.

111. Sempionatto JR, Lasalde Ramirez JA, Mahato K, Wang J, Gao W. Wearable chemical sensors for biomarker discovery in the omics era. Nat Rev Chem. 2022 Dec;6(12):899-915. doi: 10.1038/s41570-022-00439-w, PMID 37117704, PMCID PMC9666953.

112. Pal A, Goswami D, Cuellar HE, Castro B, Kuang S, Martinez RV. Early detection and monitoring of chronic wounds using low cost omniphobic paper based smart bandages. Biosens Bioelectron. 2018 Oct 15;117:696-705. doi: 10.1016/j.bios.2018.06.060, PMID 30014943.

113. Messina PV, Pistonessi BD, Belen F. Nanophase ceramic particles in bone regenerative therapeutics: theranostic platforms for bone disorders. In: inorganic nanosystems. Elsevier; 2023 Jan 1. p. 437-71. doi: 10.1016/B978-0-323-85784-0.00015-7.

114. Sharma A, AvinashJangam A, Low Yung Shen J, Ahmad A, Arepally N, Carlton H, Ivkov R, Attaluri A. Design of a temperature feedback controlled automated magnetic hyperthermia therapy device. Front Therm Eng. 2023;3:1131262. doi: 10.3389/fther.2023.1131262, PMID 36945684.

115. Bettucci O, Matrone GM, Santoro F. Conductive polymer based bioelectronic platforms toward sustainable and biointegrated devices: a journey from skin to brain across human body interfaces. Adv Mater Technol. 2022 Feb;7(2):2100293. doi: 10.1002/admt.202100293.

116. Feiner R, Dvir T. Tissue electronics interfaces: from implantable devices to engineered tissues. Nat Rev Mater. 2018;3(1):1-6. doi: 10.1038/natrevmats.2017.76.

117. Oh S, Jekal J, Liu J, Kim J, Park JU, Lee T. Bioelectronic implantable devices for physiological signal recording and closed loop neuromodulation. Adv Funct Materials. 2024 Oct;34(41):2403562. doi: 10.1002/adfm.202403562.

118. Yarali E, Mirzaali MJ, Ghalayaniesfahani A, Accardo A, Diaz Payno PJ, Zadpoor AA. 4D printing for biomedical applications. Adv Mater. 2024 Aug;36(31):e2402301. doi: 10.1002/adma.202402301, PMID 38580291.

119. Ashammakhi N, Ahadian S, Zengjie F, Suthiwanich K, Lorestani F, Orive G. Advances and future perspectives in 4D bioprinting. Biotechnol J. 2018 Dec;13(12):e1800148. doi: 10.1002/biot.201800148, PMID 30221837, PMCID PMC6433173.

120. Agarwal T, Hann SY, Chiesa I, Cui H, Celikkin N, Micalizzi S. 4D printing in biomedical applications: emerging trends and technologies. J Mater Chem B. 2021;9(37):7608-32. doi: 10.1039/D1TB01335A, PMID 34586145.

121. Lu S, Feng W, Yao X, Song X, Guo J, Chen Y. Microorganism enabled photosynthetic oxygeneration and ferroptosis induction reshape tumor microenvironment for augmented nanodynamic therapy. Biomaterials. 2022 Aug;287:121688. doi: 10.1016/j.biomaterials.2022.121688, PMID 35926358.

122. Tang Z, Liu Y, He M, Bu W. Chemodynamic therapy: tumour microenvironment mediated Fenton and fenton like reactions. Angew Chem Int Ed Engl. 2019 Jan 21;58(4):946-56. doi: 10.1002/anie.201805664, PMID 30048028.

123. Wang S, Huang P, Chen X. Hierarchical targeting strategy for enhanced tumor tissue accumulation/retention and cellular internalization. Adv Mater. 2016 Sep;28(34):7340-64. doi: 10.1002/adma.201601498, PMID 27255214, PMCID PMC5014563.

124. Fong W, Li Q, Yu J. Gut microbiota modulation: a novel strategy for prevention and treatment of colorectal cancer. Oncogene. 2020 Jun;39(26):4925-43. doi: 10.1038/s41388-020-1341-1, PMID 32514151, PMCID PMC7314664.

125. Bao Y, Verdegaal AA, Anderson BW, Barry NA, He J, Gao X. A common pathway for activation of host targeting and bacteria targeting toxins in human intestinal bacteria. mBio. 2021 Aug 31;12(4):e0065621. doi: 10.1128/mBio.00656-21, PMID 34465018, PMCID PMC8406203.

126. Hu CM, Zhang L. Therapeutic nanoparticles to combat cancer drug resistance. Curr Drug Metab. 2009 Oct;10(8):836-41. doi: 10.2174/138920009790274540, PMID 20214578.

127. Estelrich J, Escribano E, Queralt J, Busquets MA. Iron oxide nanoparticles for magnetically guided and magnetically responsive drug delivery. Int J Mol Sci. 2015 Apr 10;16(4):8070-101. doi: 10.3390/ijms16048070, PMID 25867479, PMCID PMC4425068.

128. Fomina N, Sankaranarayanan J, Almutairi A. Photochemical mechanisms of light triggered release from nanocarriers. Adv Drug Deliv Rev. 2012 Aug;64(11):1005-20. doi: 10.1016/j.addr.2012.02.006, PMID 22386560, PMCID PMC3395781.

129. Mir M, Ahmed N, Rehman AU. Recent applications of PLGA based nanostructures in drug delivery. Colloids Surf B Biointerfaces. 2017 Nov 1;159:217-31. doi: 10.1016/j.colsurfb.2017.07.038, PMID 28797972.

130. Zheng C, Li M, Ding J. Challenges and opportunities of nanomedicines in clinical translation. Bio Integr. 2021 Jul 1;2(2):57. doi: 10.15212/bioi-2021-0016.

131. Barenholz Y. Doxil® the first FDA-approved nano-drug: lessons learned. J Control Release. 2012 Jun 10;160(2):117-34. doi: 10.1016/j.jconrel.2012.03.020, PMID 22484195.

132. Tibbitt MW, Dahlman JE, Langer R. Emerging frontiers in drug delivery. J Am Chem Soc. 2016 Jan 27;138(3):704-17. doi: 10.1021/jacs.5b09974, PMID 26741786.

133. Poon W, Kingston BR, Ouyang B, Ngo W, Chan WC. A framework for designing delivery systems. Nat Nanotechnol. 2020 Oct;15(10):819-29. doi: 10.1038/s41565-020-0759-5, PMID 32895522.

134. Hou Y, Jin J, Duan H, Liu C, Chen L, Huang W. Targeted therapeutic effects of oral inulin modified double layered nanoparticles containing chemotherapeutics on orthotopic colon cancer. Biomaterials. 2022 Apr;283:121440. doi: 10.1016/j.biomaterials.2022.121440, PMID 35245731.

135. Research C for DEA. Drug products including biological products that contain nanomaterials guidance for industry. In: United States Food and Drug Administration; 2022. Available from: https://www.fda.gov/regulatoryinformation/search-fda-guidancedocuments/drug-products-including-biological-products-contain-nanomaterials-guidance-industry.

136. Gholap AD, Uddin MJ, Faiyazuddin M, Omri A, Gowri S, Khalid M. Advances in artificial intelligence for drug delivery and development: a comprehensive review. Comput Biol Med. 2024 Aug;178:108702. doi: 10.1016/j.compbiomed.2024.108702, PMID 38878397.

Published

07-09-2025

How to Cite

SUBRAMANIAN, J., PADHY, R., ARUN, J., MURTHANNAGARI, V. R., & GNK, G. (2025). STIMULI-RESPONSIVE DRUG DELIVERY SYSTEMS: EXTENSIVE OVERVIEW. International Journal of Applied Pharmaceutics, 17(5), 94–106. https://doi.org/10.22159/ijap.2025v17i5.54389

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Review Article(s)

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