SOD1 nanozyme with reduced toxicity and MPS accumulation

Area of Science:

• Biomaterials Science
• Nanotechnology
• Neuroscience

Background:

• Copper/Zinc superoxide dismutase (SOD1) nanozymes were previously formulated using poly(ethylene glycol)-b-poly(L-lysine) (PEG-PLL).
• Further development is needed for improved biocompatibility and targeted delivery of nano-therapeutics.

Purpose of the Study:

• To develop and characterize a novel SOD1 nanozyme using PEG-b-poly(aspartate diethyltriamine) (PEG-DET) for enhanced chronic dosing.
• To compare the efficacy and biodistribution of PEG-DET nanozymes against PEG-PLL nanozymes.
• To evaluate the therapeutic potential of the new nanozyme in models of ischemic stroke and amyotrophic lateral sclerosis (ALS).

Main Methods:

• Synthesis and characterization of spherical, hollow PEG-DET nanozymes.
• In vitro assessment of cellular tolerability with brain microvessel endothelial/neuronal cells.
• In vivo evaluation in mouse models of ischemic stroke and mutant SOD1 (G93A) ALS.
• Analysis of nanoparticle accumulation in liver and spleen.

Main Results:

• The PEG-DET nanozyme exhibited favorable colloidal properties and was better tolerated by neural cells compared to PEG-PLL.
• Reduced accumulation in the liver and spleen was observed with the PEG-DET formulation.
• Significant reduction (>50%) in infarct volumes was achieved in the ischemic stroke model.
• No significant effect was observed in preventing neuromuscular junction denervation in the ALS mouse model.

Conclusions:

• PEG-DET represents a promising polymer for developing biocompatible nano-therapeutics with reduced mononuclear phagocyte system (MPS) accumulation.
• The polymer structure significantly influences the biodistribution and cellular interactions of polyion complex nanozymes.
• While effective for acute conditions like stroke, further optimization is required for chronic neurodegenerative diseases such as ALS.