Polymeric Nanozyme with SOD Activity Capable of Inhibiting Self‐ and Metal‐Induced α‐Synuclein Aggregation

• Published in: Chemistry : a European journal 2024-07, Vol.30 (37), p.e202401331-n/a
• Main Authors: Martínez‐Camarena, Álvaro, Bellia, Francesco, Paz Clares, M., Vecchio, Graziella, Nicolas, Julien, García‐España, Enrique
• Format: Article
• Language: English
• Subjects: Aggregation; alpha-Synuclein - chemistry; alpha-Synuclein - metabolism; Biodegradation; Chelating Agents - chemistry; Chelating Agents - pharmacology; Chemical Sciences; Copper - chemistry; Fibrils; Humans; Ligands; Movement disorders; Nanoparticles; Nanoparticles - chemistry; Nanozyme; Neurodegenerative diseases; Oxidative stress; Oxidative Stress - drug effects; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson's disease; Polyesters - chemistry; Polyethylene Glycols - chemistry; Polymers; Polymers - chemistry; Polymers - pharmacology; Protein Aggregates - drug effects; Superoxide dismutase; Superoxide Dismutase - chemistry; Superoxide Dismutase - metabolism; Superoxide dismutase activity; Synuclein; α-Synuclein
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202401331

Despite decades of research, Parkinson's disease is still an idiopathic pathology for which no cure has yet been found. This is partly explained by the multifactorial character of most neurodegenerative syndromes, whose generation involves multiple pathogenic factors. In Parkinson's disease, two of the most important ones are the aggregation of α‐synuclein and oxidative stress. In this work, we address both issues by synthesizing a multifunctional nanozyme based on grafting a pyridinophane ligand that can strongly coordinate CuII, onto biodegradable PEGylated polyester nanoparticles. The resulting nanozyme exhibits remarkable superoxide dismutase activity together with the ability to inhibit the self‐induced aggregation of α‐synuclein into amyloid‐type fibrils. Furthermore, the combination of the chelator and the polymer produces a cooperative effect whereby the resulting nanozyme can also halve CuII‐induced α‐synuclein aggregation. A multifunctional polymeric nanozyme capable to strongly coordinate CuII is designed, generating complexes with a prominent superoxide dismutase activity. Moreover, the combination of the polymeric platform with the chelator allows the nanozyme to perform its second activity: inhibition of both the self‐ and metal‐induced aggregation of α‐synuclein peptides.