Polyol-Functionalized Manganese-Based Nanoparticles: From Insulin Amyloid Inhibition to Nanozyme-Mediated Antioxidant Activity.

Insulin amyloidosis poses challenges in diabetes therapy and biopharmaceuticals handling. Here, functionalized manganese-based nanoparticles (MnCO3@TEG, MnCO3@OAm, MnOHCO3@TEG, MnO2/Mn2O3@TEG, and Mn3O4@PG) were synthesized via solvothermal routes and evaluated in vitro using a fresh insulin aspart formulation (NovoRapid) and a separately aged insulin glargine formulation (Lantus). Structural and colloidal characterization (ATR-FTIR, XRD, TGA, DLS, zeta potential) confirmed phase purity and distinct surface profiles. In the fresh insulin aspart system, all nanoparticles extended the nucleation lag phase, with MnCO3@TEG delaying fibrillogenesis from 21.16 h to 105.41 h. In the aged insulin glargine system containing pre-existing ThT-positive aggregates, small, negatively charged nanoparticles (MnOHCO3@TEG, Mn3O4@PG) re-established a distinct lag phase and suppressed further aggregation. In the ThT decay assays, highly dispersed Mn3O4@PG produced the largest decrease in amyloid-associated fluorescence, to ~40% of the initial signal, whereas large clusters (MnO2/Mn2O3@TEG, 624 nm) produced a smaller decrease; limited access arising from steric effects is one possible explanation. Additionally, structural hydroxyl groups and high colloidal stability enabled MnOHCO3@TEG (-38.7 mV) to exhibit superior catalase-like H2O2 scavenging (42.27% inhibition at 250 μg/mL). Overall, fine-tuning nanoparticle size, surface charge, and core composition may offer a promising dual-action strategy for targeting insulin amyloidosis and associated oxidative stress across different stages of fibril formation, while further structural characterization and biological safety studies are needed to establish its therapeutic relevance.