This study aimed to evaluate the effect of enriched polyphenols-loaded alginate nanoparticles (EP-loaded AlgNP) on streptozotocin (STZ)-induced Rin-5F cells. The alginate nanoparticles of enriched polyphenols from Desmodium gangeticum leaves were synthesised by ionic-gelation process using sodium alginate as biopolymer. The nanoparticles were characterized in terms of their size, morphology using HR-TEM, FESEM, Zeta potential, and FTIR. Our findings showed that the formulated EP-loaded AlgNP exhibited spherical particles (<
100 nm) with a zeta potential of -48.8 mV. The total polyphenol content (TPC) and the biological activities of EP-loaded AlgNP showed significant stability throughout 12-months compared to EP (p <
0.05). The EP-loaded AlgNP at pH 7.4 showed optimal TPC release and followed Korsmeyer-Peppas model. The bio-accessibility of EP-loaded AlgNP was also enhanced under simulated gastrointestinal condition. In vitro experiments revealed that EP-loaded AlgNP enhanced insulin secretion impaired by STZ and improved the cell viability. Further, it mitigated oxidative stress by suppressing activation of NF-κB and upregulated mRNA expression of insulin signaling molecules like IR, IRS-1, and GLUT 2 in STZ-induced RIN-5F cells (p <
0.0001). Overall, the synthesis of EP-loaded AlgNP could be a promising approach and might be an effective therapeutic option for treating diabetes.