Glucose-Responsive "Smart" Insulin Delivery Systems: Advances in Polymeric Nanoparticles and Hydrogels for Closed-Loop Management of Type 1 and Type 2 Diabetes

Punam Nikam; Waghamare Suresh; Sakshi Ambhore

doi:10.52711/2349-2988.2026.00050

Research Journal of Science and Technology

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2349-2988 (Online)
0975-4393 (Print)

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Glucose-Responsive "Smart" Insulin Delivery Systems: Advances in Polymeric Nanoparticles and Hydrogels for Closed-Loop Management of Type 1 and Type 2 Diabetes

Author(s): Punam Nikam, Waghamare Suresh, Sakshi Ambhore

Email(s): waghasuresh@gmail.com

DOI: 10.52711/2349-2988.2026.00050

Address: Punam Nikam, Waghamare Suresh*, Sakshi Ambhore
Department of Pharmaceutics, Rashtriya College of Pharmacy, Hatnoor, Maharashtra, India – 431103.
*Corresponding Author

Published In: Volume - 18, Issue - 4, Year - 2026

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ABSTRACT:
Insulin replacement therapy is required to maintain normoglycemia and reduce the incidence of hypoglycemia for patients with Type 1 diabetes and in advanced Type 2 diabetes. Current treatment methods, such as daily insulin injection, insulin pumps and continuous subcutaneous insulin infusion, are not able to mimic the glucose-dependent insulin secretion of a healthy pancreas, leading to suboptimal blood glucose control and higher complication rates. A novel alternative is the closed-loop glucose-responsive insulin delivery system, which can autonomously control insulin secretion based on the blood glucose concentration. This review focuses on the recent developments of polymeric nanoparticles and hydrogel based smart insulin delivery system. The most important glucose sensing strategies involve enzymatic sensors with glucose oxidase (GOx), chemical sensors with phenylboronic acid (PBA) and mixed/cooperative sensors. In terms of insulin stability, controlled release, and biocompatibility, polymeric nanoparticles such as PLGA, chitosan, and hybrid nanocarriers, in addition to injectable, bulk, micro/nanogel and microneedle-integrated hydrogels are seen to improve the insulin properties. These innovations are in the early stages of development, including PBA-functionalized silk fibroin hydrogels, multi-responsive nanocarriers, and AI-driven closed-loop systems, with promising preclinical results. Although many challenges remain in the form of response delay, protein instability, immunogenicity, scalability, and clinical translation, these glucose responsive biomaterials show great promise in personalized diabetes management and enhanced long-term therapeutic efficacy

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Cite this article:
Punam Nikam, Waghamare Suresh, Sakshi Ambhore. Glucose-Responsive "Smart" Insulin Delivery Systems: Advances in Polymeric Nanoparticles and Hydrogels for Closed-Loop Management of Type 1 and Type 2 Diabetes. Research Journal of Science and Technology. 2026; 18(4):355-6. doi: 10.52711/2349-2988.2026.00050

Cite(Electronic):
Punam Nikam, Waghamare Suresh, Sakshi Ambhore. Glucose-Responsive "Smart" Insulin Delivery Systems: Advances in Polymeric Nanoparticles and Hydrogels for Closed-Loop Management of Type 1 and Type 2 Diabetes. Research Journal of Science and Technology. 2026; 18(4):355-6. doi: 10.52711/2349-2988.2026.00050 Available on: https://www.rjstonline.com/AbstractView.aspx?PID=2026-18-4-6

12. REFERENCES:
1. Karaoglu IC, Duymaz D, Rashid MM, Kizilel S. Immune-evasive beta cells in type 1 diabetes: innovations in genetic engineering, biomaterials, and computational modeling. Front Immunol 2025; 16: 1618086. https://doi.org/10.3389/fimmu.2025.1618086.
2. S.U W, Mishra A, S.G K. Recent Advances in Polymeric Microparticles - Based Drug Delivery Systems for the Treatment of Diabetes. Research Journal of Pharmacy and Technology. 2025: 1611–8. https://doi.org/10.52711/0974-360X.2025.00231.
3. Halstrom A, Moledina I, Peragallo-Dittko V, Ancona K, Islam S, Klek S, et al. Continuous Subcutaneous Insulin Infusions vs. Multiple Daily Injections of Insulin in Hospitalized Patients: Glycemic Trends in the First 24 Hours of Admission. J Diabetes Sci Technol 2022;16: 683–8. https://doi.org/10.1177/1932296821991136.
4. Templer S. Closed-Loop Insulin Delivery Systems: Past, Present, and Future Directions. Front Endocrinol. 2022; 13: 919942. https://doi.org/10.3389/fendo.2022.919942.
5. Pal S, Rakshit T, Saha S, Jinagal D. Glucose-Responsive Materials for Smart Insulin Delivery: From Protein-Based to Protein-Free Design. ACS Mater Au. 2025; 5: 239–52. https://doi.org/10.1021/acsmaterialsau.4c00138.
6. Delgado-Pujol EJ, Martínez G, Casado-Jurado D, Vázquez J, León-Barberena J, Rodríguez-Lucena D, et al. Hydrogels and Nanogels: Pioneering the Future of Advanced Drug Delivery Systems. Pharmaceutics 2025; 17: 215. https://doi.org/10.3390/pharmaceutics17020215.
7. Fontana G, Innamorati G, Giacomello L. Nanoparticle-Based Oral Insulin Delivery: Challenges, Advances, and Future Directions. Pharmaceutics 2025; 17: 1563. https://doi.org/10.3390/pharmaceutics17121563.
8. Kudhekar A, Waghamare S, Kadag P. Smart Separation Techniques: AI-Based Optimization in the Formulation Process. In: Waghamare S, Gaikwad A, Jahed S, Khanage S, editors. Artificial Intelligence in Preformulation Studies: Predictive Methods For Modern Pharmaceutical Development, Deep Science Publishing; 2026. https://doi.org/10.70593/978-93-7185-262-3_4.
9. Webber MJ, Anderson DG. Smart approaches to glucose-responsive drug delivery. Journal of Drug Targeting. 2015; 23: 651–5. https://doi.org/10.3109/1061186X.2015.1055749.
10. Berger C, Zdzieblo D. Glucose transporters in pancreatic islets. Pflugers Arch - Eur J Physiol. 2020; 472:1249–72. https://doi.org/10.1007/s00424-020-02383-4.
11. Morey M, Srivastava A, Pandit A. Glucose-Responsive Gene Delivery at Physiological pH through Tertiary-Amine Stabilized Boronate-PVA Particles Synthesized by One-Pot Reaction. Pharmaceutics. 2021;13:62. https://doi.org/10.3390/pharmaceutics13010062.
12. Mohanty AR, Ravikumar A, Peppas NA. Recent advances in glucose-responsive insulin delivery systems: novel hydrogels and future applications. Regenerative Biomaterials. 2022;9:rbac056. https://doi.org/10.1093/rb/rbac056.
13. Wang C, Lin B, Zhu H, Bi F, Xiao S, Wang L, et al. Recent Advances in Phenylboronic Acid-Based Gels with Potential for Self-Regulated Drug Delivery. Molecules. 2019;24:1089. https://doi.org/10.3390/molecules24061089.
14. Terriac L, Helesbeux J-J, Maugars Y, Guicheux J, Tibbitt MW, Delplace V. Boronate Ester Hydrogels for Biomedical Applications: Challenges and Opportunities. Chem Mater 2024;36:6674–95. https://doi.org/10.1021/acs.chemmater.4c00507.
15. Bercea M, Lupu A. Recent Insights into Glucose-Responsive Concanavalin A-Based Smart Hydrogels for Controlled Insulin Delivery. Gels. 2024; 10: 260. https://doi.org/10.3390/gels10040260.
16. Sullivan MV, Allabush F, Flynn H, Balansethupathy B, Reed JA, Barnes ET, et al. Highly Selective Aptamer‐Molecularly Imprinted Polymer Hybrids for Recognition of SARS‐CoV‐2 Spike Protein Variants. Global Challenges. 2023; 7: 2200215. https://doi.org/10.1002/gch2.202200215.
17. Yang J, Cao Z. Glucose-responsive insulin release: Analysis of mechanisms, formulations, and evaluation criteria. Journal of Controlled Release 2017; 263: 231–9. https://doi.org/10.1016/j.jconrel.2017.01.043.
18. Liu W, Zhang J, Wang Y, He Y, Wang Y, Wei X, et al. Long-acting glucose-responsive insulin with swift onset-of-action. Journal of Controlled Release. 2025; 383: 113826. https://doi.org/10.1016/j.jconrel.2025.113826.
19. Kirkby M, Hutton ARJ, Donnelly RF. Microneedle Mediated Transdermal Delivery of Protein, Peptide and Antibody Based Therapeutics: Current Status and Future Considerations. Pharm Res 2020; 37: 117. https://doi.org/10.1007/s11095-020-02844-6.
20. Latres E, Finan DA, Greenstein JL, Kowalski A, Kieffer TJ. Navigating Two Roads to Glucose Normalization in Diabetes: Automated Insulin Delivery Devices and Cell Therapy. Cell Metabolism. 2019; 29: 545–63. https://doi.org/10.1016/j.cmet.2019.02.007.
21. Wang Y, Li H, Rasool A, Wang H, Manzoor R, Zhang G. Polymeric nanoparticles (PNPs) for oral delivery of insulin. J Nanobiotechnol. 2024; 22: 1. https://doi.org/10.1186/s12951-023-02253-y.
22. Geszke-Moritz M, Moritz M. Biodegradable Polymeric Nanoparticle-Based Drug Delivery Systems: Comprehensive Overview, Perspectives and Challenges. Polymers. 2024; 16: 2536. https://doi.org/10.3390/polym16172536.
23. Mishra A, Waghamare S, Khanage SG. Acarbose-Loaded PLGA Microspheres: Efficient Encapsulation and Controlled Release. J Drug Delivery Ther. 2025; 15: 30–40. https://doi.org/10.22270/jddt.v15i6.7165.
24. Sivadasan D, Sultan MH, Madkhali O, Almoshari Y, Thangavel N. Polymeric Lipid Hybrid Nanoparticles (PLNs) as Emerging Drug Delivery Platform—A Comprehensive Review of Their Properties, Preparation Methods, and Therapeutic Applications. Pharmaceutics. 2021; 13: 1291. https://doi.org/10.3390/pharmaceutics13081291.
25. Hernández-Giottonini KY, Rodríguez-Córdova RJ, Gutiérrez-Valenzuela CA, Peñuñuri-Miranda O, Zavala-Rivera P, Guerrero-Germán P, et al. PLGA nanoparticle preparations by emulsification and nanoprecipitation techniques: effects of formulation parameters. RSC Adv. 2020; 10: 4218–31. https://doi.org/10.1039/C9RA10857B.
26. Ji K, Wei X, Kahkoska AR, Zhang J, Zhang Y, Xu J, et al. An orally administered glucose-responsive polymeric complex for high-efficiency and safe delivery of insulin in mice and pigs. Nat Nanotechnol 2024;19:1880–91. https://doi.org/10.1038/s41565-024-01764-5.
27. Li S, Wang Q, Jia Z, Da M, Zhao J, Yang R, et al. Recent advances in glucose oxidase-based nanocarriers for tumor targeting therapy. Heliyon 2023; 9: e20407. https://doi.org/10.1016/j.heliyon.2023.e20407.
28. Zhang X, Peng C, Zhang W, Wang N, Li J, He W, et al. Glucose-Responsive Polyzwitterionic Nanoparticles with Enhanced and Targeted Intestinal Epithelial Absorption for Oral Insulin Delivery. ACS Nano. 2025; 19: 26871–81. https://doi.org/10.1021/acsnano.5c07679.
29. Sharmah B, Afzal NU, Loying R, Roy A, Kalita J, Das J, et al. Glucose-Responsive Insulin Delivery via Surface-Functionalized Titanium Dioxide Nanoparticles: A Promising Theragnostic against Diabetes Mellitus. ACS Appl Bio Mater 2025; 8: 475–87. https://doi.org/10.1021/acsabm.4c01426.
30. Ghasemi A, Jeddi S. Streptozotocin as a tool for induction of rat models of diabetes: a practical guide. EXCLI Journal. 2023. https://doi.org/10.17179/EXCLI2022-5720.
31. Pridgen EM, Alexis F, Farokhzad OC. Polymeric Nanoparticle Technologies for Oral Drug Delivery. Clinical Gastroenterology and Hepatology. 2014; 12: 1605–10. https://doi.org/10.1016/j.cgh.2014.06.018.
32. Wang X, Wang K, Fang Y, Zhang Y, Yi L, Li X, et al. Strategies for overcoming multiple barriers of oral administration of protein and peptide therapeutics. Materials Today Bio. 2026; 37: 102763. https://doi.org/10.1016/j.mtbio.2026.102763.
33. Ho T-C, Chang C-C, Chan H-P, Chung T-W, Shu C-W, Chuang K-P, et al. Hydrogels: Properties and Applications in Biomedicine. Molecules. 2022; 27: 2902. https://doi.org/10.3390/molecules27092902.
34. Suresh W, Kudhekar A. Healing by Design: Bioactive Hydrogels as Intelligent Tissue Architects. Asian Journal of Pharmacy and Technology. 2025: 377–84. https://doi.org/10.52711/2231-5713.2025.00056.
35. Lee Y, Kim M, Kim N, Byun S, Seo S, Han JY. Injectable Hydrogel Systems for Targeted Drug Delivery: From Site-Specific Application to Design Strategy. Applied Sciences. 2025; 15: 11599. https://doi.org/10.3390/app152111599.
36. Abourehab MAS, Rajendran RR, Singh A, Pramanik S, Shrivastav P, Ansari MJ, et al. Alginate as a Promising Biopolymer in Drug Delivery and Wound Healing: A Review of the State-of-the-Art. IJMS. 2022; 23: 9035. https://doi.org/10.3390/ijms23169035.
37. Liu J, Yi X, Zhang J, Yao Y, Panichayupakaranant P, Chen H. Recent Advances in the Drugs and Glucose-Responsive Drug Delivery Systems for the Treatment of Diabetes: A Systematic Review. Pharmaceutics. 2024; 16: 1343. https://doi.org/10.3390/pharmaceutics16101343.
38. Maity B, Moorthy H, Govindaraju T. Glucose-Responsive Self-Regulated Injectable Silk Fibroin Hydrogel for Controlled Insulin Delivery. ACS Appl Mater Interfaces. 2023; 15: 49953–63. https://doi.org/10.1021/acsami.3c07060.
39. Kage PP, Somvanshi MS, Sarvadnya AA, Patil RD, Jadhav AG, Bendale AR. Thermosensitive Hydrogels for Drug Delivery Systems: A Comprehensive Review. Biosci Biotech Res Asia. 2026 2026;1:160. https://doi.org/10.13005/bbra/3488.
40. Xia B, Liu Y, Xing Y, Shi Z, Pan X. Biodegradable Medical Implants: Reshaping Future Medical Practice. Advanced Science. 2025; 12: e08014. https://doi.org/10.1002/advs.202508014.
41. Datta D, Colaco V, Nison M, H AP, Bandi SP, Dhas N, et al. Smart microdevices for biomedical drug delivery: endogenous stimuli as the key to safer therapeutics. RSC Adv. 2026; 16: 14878–935. https://doi.org/10.1039/D5RA09767C.
42. Sidki AS, Highton PJ, O’Mahoney LL, Wilkinson TJ. Hybrid closed‐loop insulin delivery improves glycaemic control compared with sensor‐augmented pump therapy: A meta‐analysis of ‘free‐living’ randomised trials in type 1 diabetes. Diabet Med. 2026; 43: e70210. https://doi.org/10.1111/dme.70210.
43. Chen S, Matsumoto H, Moro-oka Y, Tanaka M, Miyahara Y, Suganami T, et al. Smart Microneedle Fabricated with Silk Fibroin Combined Semi-interpenetrating Network Hydrogel for Glucose-Responsive Insulin Delivery. ACS Biomater Sci Eng. 2019; 5: 5781–9. https://doi.org/10.1021/acsbiomaterials.9b00532.
44. Pathak V, Pathak NM, O’Neill CL, Guduric-Fuchs J, Medina RJ. Therapies for Type 1 Diabetes: Current Scenario and Future Perspectives. Clin Med Insights Endocrinol Diabetes. 2019; 12: 1179551419844521. https://doi.org/10.1177/1179551419844521.
45. Zhang S, Ge G, Qin Y, Li W, Dong J, Mei J, et al. Recent advances in responsive hydrogels for diabetic wound healing. Materials Today Bio. 2023; 18: 100508. https://doi.org/10.1016/j.mtbio.2022.100508.
46. Pavlou P, Anandhakrishnan A, Athanasiadou KI, Brackenridge A, Liu Y, Kariyawasam D, et al. Discordant real‐world glycaemic outcomes with OMNIPODTM 5 and MINIMEDTM 780G in adults with type 1 diabetes: Why validated measures matter. Diabetes Obesity Metabolism. 2026; 28: 3424–8. https://doi.org/10.1111/dom.70480.
47. Kaushal JB, Raut P, Kumar S. Organic Electronics in Biosensing: A Promising Frontier for Medical and Environmental Applications. Biosensors. 2023; 13: 976. https://doi.org/10.3390/bios13110976.
48. Segneanu A-E, Bejenaru LE, Bejenaru C, Blendea A, Mogoşanu GD, Biţă A, et al. Advancements in Hydrogels: A Comprehensive Review of Natural and Synthetic Innovations for Biomedical Applications. Polymers. 2025; 17: 2026. https://doi.org/10.3390/polym17152026.
49. Morais JM, Papadimitrakopoulos F, Burgess DJ. Biomaterials/Tissue Interactions: Possible Solutions to Overcome Foreign Body Response. AAPSJ. 2010; 12: 188–96. https://doi.org/10.1208/s12248-010-9175-3.
50. Suresh W, Salpure S, Nikam M. The Gut Microbiome and Diabetes: A Review of Current Understanding and Therapeutic Implications. RJPPD. 2025: 295–303. https://doi.org/10.52711/2321-5836.2025.00046.
51. Locke AK, Cummins BM, Abraham AA, Coté GL. PEGylation of Concanavalin A to Improve Its Stability for an In Vivo Glucose Sensing Assay. Anal Chem. 2014; 86: 9091–7. https://doi.org/10.1021/ac501791u.
52. Vu LQ, Chiu I-H, Hoang CTH, Bui NTQ, Suhail M, Wu P-C. Injectable thermosensitive hydrogel-based sustained delivery system for anti-diabetic peptides in type 2 diabetes mellitus therapy: A review. Biomedicine & Pharmacotherapy. 2026; 198: 119249. https://doi.org/10.1016/j.biopha.2026.119249.
53. Saikawa R, Yamada H, Suzuki D, Amamoto M, Matsumoto Y, Funazaki S, et al. Risk Factors of Hypoglycemic Encephalopathy and Prolonged Hypoglycemia in Patients with Severe Hypoglycemia. J Clin Med Res. 2019; 11: 213–8. https://doi.org/10.14740/jocmr3728.
54. Panayiotidis M, Tsolas O, Galaris D. Glucose oxidase-produced H2O2 induces Ca2+-dependent DNA damage in human peripheral blood lymphocytes. Free Radical Biology and Medicine. 1999; 26: 548–56. https://doi.org/10.1016/S0891-5849(98)00249-4.
55. Li S, Hou X, Ma Y, Wang Z. Phenylboronic-acid-based Functional Chemical Materials for Fluorescence Imaging and Tumor Therapy. ACS Omega. 2022; 7: 2520–32. https://doi.org/10.1021/acsomega.1c06558.
56. Suvarna P, Likhith K, Nison M, Datta D, Pai VR, Chidananda C, et al. Responsive to revolutionary: thermoresponsive hydrogels pioneering drug delivery and tissue engineering. Materials & Design. 2026; 266: 115973. https://doi.org/10.1016/j.matdes.2026.115973.
57. Tian J, Song X, Wang Y, Cheng M, Lu S, Xu W, et al. Regulatory perspectives of combination products. Bioactive Materials. 2022; 10: 492–503. https://doi.org/10.1016/j.bioactmat.2021.09.002.
58. Chowdhury S, Sarkar S, Das A, Kar K, Chakraborty P. Next-generation smart drug delivery: Biosensor-integrated closed-loop therapeutics (CLT) for regenerative medicine. Next Bioengineering 2026;2:100027. https://doi.org/10.1016/j.nxbio.2026.100027.
59. Alghareeb S, Asare-Addo K, Conway BR, Adebisi AO. PLGA nanoparticles for nasal drug delivery. Journal of Drug Delivery Science and Technology. 2024; 95: 105564. https://doi.org/10.1016/j.jddst.2024.105564.
60. Tong MQ, Luo LZ, Xue PP, Han YH, Wang LF, Zhuge DL, et al. Glucose-responsive hydrogel enhances the preventive effect of insulin and liraglutide on diabetic nephropathy of rats. Acta Biomaterialia. 2021; 122: 111–32. https://doi.org/10.1016/j.actbio.2021.01.007.
61. Lakharwal P, Bose R, Thakur S, Byun H-S. Smart nanomaterial-based therapeutics for the management of diabetes and its complications. Materials & Design. 2026; 264: 115805. https://doi.org/10.1016/j.matdes.2026.115805.
62. Jacob S, Kather FS, Satyam SM, Boddu SHS, Assaf F, Allam THA, et al. Injectable In Situ Thermoreversible Gel Depot System of Lidocaine Nanoemulsion for Prolonged Anesthetic Activity in Dental and Operative Procedures. Pharmaceutics. 2025; 17: 1355. https://doi.org/10.3390/pharmaceutics17101355.
63. Mandal B, Bhattacharjee H, Mittal N, Sah H, Balabathula P, Thoma LA, et al. Core–shell-type lipid–polymer hybrid nanoparticles as a drug delivery platform. Nanomedicine: Nanotechnology, Biology and Medicine. 2013; 9: 474–91. https://doi.org/10.1016/j.nano.2012.11.010.
64. Rajamohan R, Sun S. Nanostructured Materials in Glucose Biosensing: From Fundamentals to Smart Healthcare Applications. Biosensors. 2025; 15: 658. https://doi.org/10.3390/bios15100658.
65. Nunziata G, Pollonio D, Lacroce E, Rossi F. Smart pH-Responsive polymers in biomedical Applications: Nanoparticles, hydrogels, and emerging hybrid platforms. Materials Today Chemistry. 2025; 49: 103063. https://doi.org/10.1016/j.mtchem.2025.103063.
66. Vora LK, Sabri AH, Naser Y, Himawan A, Hutton ARJ, Anjani QK, et al. Long-acting microneedle formulations. Advanced Drug Delivery Reviews. 2023; 201: 115055. https://doi.org/10.1016/j.addr.2023.115055.
67. Teymoori M, Poorkhalil A, Farrokhzad H, Tabesh H. Glucose responsive microneedle patch using a reversible and an irreversible crosslinking agent. Results in Engineering. 2025; 27: 106134. https://doi.org/10.1016/j.rineng.2025.106134.
68. Li Z, Chen L, Yang S, Han J, Zheng Y, Chen Z, et al. Glucose and pH dual-responsive hydrogels with antibacterial, reactive oxygen species scavenging, and angiogenesis properties for promoting the healing of infected diabetic foot ulcers. Acta Biomaterialia. 2024; 190: 205–18. https://doi.org/10.1016/j.actbio.2024.10.020.
69. Zhu P, Zhou Z, Ding J, Dou Z, Lu B, Nan K, et al. Wearable devices for detection and treatment of chronic wounds. Cell Reports Physical Science. 2026; 7: 103171. https://doi.org/10.1016/j.xcrp.2026.103171.
70. Jung W, Ryu H, Chae J, Yun H. Fractal Kinetic Implementation in Population Pharmacokinetic Modeling. Pharmaceutics. 2023; 15: 304. https://doi.org/10.3390/pharmaceutics15010304.