A Degradable Nanosystem Based on Small Gold Nanoparticles and Albumin for Amyloid Aggregation Inhibition

Background/Objectives: Beta amyloid (Aβ) aggregates play a central role in the pathophysiology of Alzheimer's disease (AD), and their detection and modulation remain major challenges in developing effective therapeutic and diagnostic strategies. Previously, gold nanoparticles with plasmonic and optical properties in the near-infrared (NIR) region and photothermal capabilities have been designed for detecting and disaggregating Aβ aggregates. However, these systems often face limitations related to biodegradability, long-term accumulation, and safety. In this work, a degradable NIR-responsive nanosystem based on small gold nanoparticles (sAuNPs), potentially excretable due to their small size, encapsulated within bovine serum albumin (BSA) and functionalized with the all-D peptide D3, was developed to inhibit Aβ aggregation. Methods: sAuNPs (~5-6 nm), functionalized with HS-PEG-NH₂, were encapsulated into BSA nanoparticles using a desolvation method and subsequently conjugated to D3, resulting in the nanosystem f-sAuNPs-BSANPs-D3. The nanosystem was characterized by UV-Vis-NIR spectroscopy, dynamic light scattering, zeta potential analysis, electron microscopy, and nanoparticle tracking analysis. The effects of the nanosystem on Aβ_1-42 aggregation were evaluated using a thioflavin T assay and electron microscopy. Additionally, the effects of f-sAuNPs-BSANPs-D3 on cell viability and its stability against trypsin digestion were assessed. Results: The nanosystem exhibited a measurable photothermal response under NIR irradiation and significantly reduced fibril formation. It did not affect the viability of SH-SY5Y neuronal cells at the tested concentrations. Trypsin incubation experiments demonstrated that the nanosystem remained stable at low enzyme concentrations mimicking plasma conditions, whereas higher enzyme concentrations induced degradation of the albumin matrix and subsequent disaggregation of sAuNPs. Conclusions: Overall, this study presents a degradable, albumin-based sAuNP nanosystem with NIR-responsive properties and potential for nanomedicine applications to inhibit Aβ aggregation in AD.