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Abstract

Oral insulin has long been explored as a potential alternative to injectable insulin therapy. However, the development remains challenging due to enzymatic degradation in the gastrointestinal tract and limited intestinal absorption. Nanoparticle-based delivery systems have also been proposed as a strategy to protect insulin and improve uptake after oral administration. Therefore, this systematic review aimed to summarize recent preclinical studies investigating oral insulin nanoparticles in diabetic animal models and examine the reported pharmacological outcomes. Relevant studies were identified through database searches in PubMed, SpringerLink, and ScienceDirect using predefined keywords related to oral insulin, nanoparticles, diabetes, and animal models. Articles published between January 2021 and 2026 were screened following the predefined eligibility criteria. After removal of duplicates and records that did not meet accessibility requirements, titles and abstracts were reviewed, followed by full-text evaluation of potentially relevant studies. Non-English articles, studies without accessible full text, and analyses where insulin was not the primary intervention were excluded. A total of 16 studies met the inclusion criteria and were included in the narrative synthesis. The results showed that most investigations focused on polymer-based nanoparticles, but silica-based, biomimetic, and hybrid systems were also reported. Across studies, oral insulin nanoparticles reduced blood glucose levels in diabetic animals. The magnitude, onset, and duration of the glycemic response varied considerably among formulations. Current evidence suggested that oral insulin nanoparticles could produce pronounced glucose-lowering effects with rapid onset and sustained activity, depending on the formulation. Further standardized pharmacological evaluations in animal models were needed to assess translational potential for human application.

References

Abd-Alhussain, G. K., Alatrakji, M. Q. Y. M.-A., Ahmed, S. J., & Fawzi, H. A. (2024). Efficacy of oral insulin nanoparticles for the management of hyperglycemia in a rat model of diabetes induced with streptozotocin. Journal of Medicine and Life, 17(2), 217–225. https://doi.org/10.25122/jml-2023-0355 

Abel, E. D., Gloyn, A. L., Evans-Molina, C., Joseph, J. J., Misra, S., Pajvani, U. B., Simcox, J., Susztak, K., & Drucker, D. J. (2024). Diabetes mellitus-Progress and opportunities in the evolving epidemic. Cell, 187(15), 3789–3820. https://doi.org/10.1016/j.cell.2024.06.029 

Benyettou, F., Kaddour, N., Prakasam, T., Das, G., Sharma, S. K., Thomas, S. A., Bekhti-Sari, F., Whelan, J., Alkhalifah, M. A., Khair, M., Traboulsi, H., Pasricha, R., Jagannathan, R., Mokhtari-Soulimane, N., Gándara, F., & Trabolsi, A. (2021). In vivo oral insulin delivery via covalent organic frameworks. Chemical Science, 12(17), 6037–6047. https://doi.org/10.1039/d0sc05328g 

Cai, H., Yong, F., Li, R., Chen, J., Liu, X., Song, B., Wang, Z., Zhao, Q., & Zhong, S. (2024). Development of a pH-Sensitive Nanoparticle via Self-Assembly of Fucoidan and Protamine for the Oral Delivery of Insulin. Pharmaceutics, 16(10). https://doi.org/10.3390/pharmaceutics16101323 

Chávez-Corona, J. I., Vargas-Estrada, D., Caballero-Chacón, S. C., Peña-Corona, S. I., Bernad-Bernad, M. J., Gracia-Mora, J., Galván-Vela, D. P., Macías-Rosales, L., & Gracia-Mora, M. I. (2025). Effect and safety of modified-release insulin-loaded liposome prototypes on glycemia in experimental models of type 1 diabetes mellitus. Letters in Drug Design & Discovery, 22(2), 100012. https://doi.org/10.1016/j.lddd.2025.100012 

Cui, Z., Cui, S., Qin, L., An, Y., Zhang, X., Guan, J., Wong, T. W., & Mao, S. (2023). Comparison of virus-capsid mimicking biologic-shell-based versus polymeric-shell nanoparticles for enhanced oral insulin delivery. Asian Journal of Pharmaceutical Sciences, 18(5), 100848. https://doi.org/10.1016/j.ajps.2023.100848 

Henshaw, F. R., Dewsbury, L. S., Lim, C. K., & Steiner, G. Z. (2021). The Effects of Cannabinoids on Pro- and Anti-Inflammatory Cytokines: A Systematic Review of In Vivo Studies. Cannabis and Cannabinoid Research, 6(3), 177–195. https://doi.org/10.1089/can.2020.0105 

Heyns, I. M., Arora, M., Ganugula, R., Allamreddy, S. R., Tiwari, S., Shah, D. K., Basu, R., & Kumar, M. N. V. R. (2024). Polyester Nanoparticles with Controlled Topography for Peroral Drug Delivery Using Insulin as a Model Protein. ACS Nano, 18(18), 11863–11875. https://doi.org/10.1021/acsnano.4c01027 

Huang, X., Han, S., Chen, Z., Zhao, L., Wang, C., Guo, Q., Li, Y., & Sun, Y. (2021). Layered Double Hydroxide Modified with Deoxycholic and Hyaluronic Acids for Efficient Oral Insulin Absorption. International Journal of Nanomedicine, 16, 7861–7873. https://doi.org/10.2147/IJN.S323381 

Jia, X., Yuan, Z., Yang, Y., Huang, X., Han, N., Liu, X., Lin, X., Ma, T., Xu, B., Wang, P., & Lei, H. (2022). Multifunctional self-assembly nanoparticles originating from a small-molecule natural product for oral insulin delivery through modulating tight junctions. Journal of Nanobiotechnology, 20(1), 116. https://doi.org/10.1186/s12951-022-01260-9 

Li, J., Zhang, Y., Yu, M., Wang, A., Qiu, Y., Fan, W., Hovgaard, L., Yang, M., Li, Y., Wang, R., Li, X., & Gan, Y. (2022). The upregulated intestinal folate transporters direct the uptake of ligand-modified nanoparticles for enhanced oral insulin delivery. Acta Pharmaceutica Sinica B, 12(3), 1460–1472. https://doi.org/10.1016/j.apsb.2021.07.024 

Li, M., Wang, N., Liu, R., Zhang, X., He, W., Zhang, W., Li, J., Peng, C., & Li, Y. (2024). pH and H(2)O(2) dual-sensitive nanoparticles enable enhanced and safe glucose-responsive oral insulin delivery for diabetes mellitus treatment. Theranostics, 14(14), 5596–5607. https://doi.org/10.7150/thno.98177 

Manjunath, P. G., Ravi, N. K., Sridhar, S. K., & Nimbagal Raghavendra, N. (2025). Innovative strategies and nanocarrier approaches for enhancing the oral bioavailability of macromolecular therapeutics. Iranian Journal of Basic Medical Sciences, 28(12), 1607–1619. https://doi.org/10.22038/ijbms.2025.87167.18839 

Marinheiro, D., Martel, F., Ferreira, B. J. M. L., & Daniel-da-Silva, A. L. (2022). Silica-Based Nanomaterials for Diabetes Mellitus Treatment. Bioengineering (Basel, Switzerland), 10(1). https://doi.org/10.3390/bioengineering10010040 

Raghunath, I., Koland, M., Saoji, S. D., Bukke, S. P. N., Deshpande, N. S., Augustin, V., Rarokar, N., & Thalluri, C. (2025). Effects of piperine on intestinal permeation, pharmacodynamics, and pharmacokinetics of insulin-loaded chitosan-coated solid lipid nanoparticles in rats. Scientific Reports, 15(1), 22771. https://doi.org/10.1038/s41598-025-05137-3 

Rehmani, S., McLaughlin, C. M., Eltaher, H. M., Moffett, R. C., Flatt, P. R., & Dixon, J. E. (2023). Orally-delivered insulin-peptide nanocomplexes enhance transcytosis from cellular depots and improve diabetic blood glucose control. Journal of Controlled Release, 360, 93–109. https://doi.org/10.1016/j.jconrel.2023.06.006 

Romero-Carmona, C. E., Chávez-Corona, J. I., Lima, E., Cortés, H., Quintanar-Guerrero, D., Bernad-Bernad, M. J., Ramos-Martínez, I., Peña-Corona, S. I., Sharifi-Rad, J., & Leyva-Gómez, G. (2024). Nanoparticle and microparticle-based systems for enhanced oral insulin delivery: A systematic review and meta-analysis. Journal of Nanobiotechnology, 22(1), 802. https://doi.org/10.1186/s12951-024-03045-8 

Salarkia, E., Mehdipoor, M., Molaakbari, E., Khosravi, A., Sazegar, M. R., Salari, Z., Rad, I., Dabiri, S., Joukar, S., Sharifi, I., & Ren, G. (2023). Exploring mesoporous silica nanoparticles as oral insulin carriers: In silico and in vivo evaluation. Heliyon, 9(10), e20430. https://doi.org/10.1016/j.heliyon.2023.e20430 

Song, J. G., Lee, S. H., & Han, H.-K. (2021). Development of an M cell targeted nanocomposite system for effective oral protein delivery: Preparation, in vitro and in vivo characterization. Journal of Nanobiotechnology, 19(1), 15. https://doi.org/10.1186/s12951-020-00750-y 

Wang, S., Meng, S., Zhou, X., Gao, Z., & Piao, M. G. (2023). pH-Responsive and Mucoadhesive Nanoparticles for Enhanced Oral Insulin Delivery: The Effect of Hyaluronic Acid with Different Molecular Weights. Pharmaceutics, 15(3). https://doi.org/10.3390/pharmaceutics15030820

Wang, Y., Li, H., Rasool, A., Wang, H., Manzoor, R., & Zhang, G. (2024). Polymeric nanoparticles (PNPs) for oral delivery of insulin. Journal of Nanobiotechnology, 22(1), 1. https://doi.org/10.1186/s12951-023-02253-y 

Xia, B., Xu, F., Chen, J., Shan, S., Shen, J., Zhang, Y., Wang, J., Zhou, Z., Sun, W., Jia, Y., Zhang, Y.-L., Zhong, J., Zhang, G., Wan, Y., Hu, Z., An, W., Fan, Y., Bottini, M., Wang, J., & Liang, X.-J. (2025). Site-specific adaptive nanovesicles for oral insulin delivery. Science Advances, 11(39), eady6386. https://doi.org/10.1126/sciadv.ady6386 

Zhang, E., Zhu, H., Song, B., Shi, Y., & Cao, Z. (2024). Recent advances in oral insulin delivery technologies. Journal of Controlled Release : Official Journal of the Controlled Release Society, 366, 221–230. https://doi.org/10.1016/j.jconrel.2023.12.045                                                                                                         

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