Engineered-Macrophage-Escorted Rotaxane Nanoscavengers for Precise Diquat Detoxification

Area of Science:

• Biomaterials Engineering
• Redox Biology
• Toxicology

Background:

• Toxin poisoning, particularly from herbicides like diquat, presents a critical therapeutic challenge.
• Current treatments like hemodialysis are often passive and lack targeted efficacy.
• Reactive oxygen species (ROS) generation is a key mechanism in diquat toxicity.

Purpose of the Study:

• To develop an on-demand, bioinspired detoxification strategy for diquat poisoning.
• To design a system for active toxin neutralization and targeted delivery to the kidneys.
• To integrate antioxidant pathway activation with toxin sequestration for synergistic therapeutic effects.

Main Methods:

• Computational design of charge-neutralizing carboxymethyl α-cyclodextrin (CCD) for diquat recognition and sequestration.
• Assembly of CCD into PEG5K rotaxanes for enhanced renal targeting and stabilization with ROS-cleavable polymers.
• Encapsulation of rotaxanes into macrophages to leverage inflammatory chemotaxis.
• Incorporation of 4-octyl itaconate (4-OI) to activate the Nrf2 antioxidant pathway.

Main Results:

• The engineered system demonstrated precise accumulation in the kidneys of diquat-poisoned mice.
• Significant reduction in diquat-induced ROS generation and associated tissue damage was observed.
• Markedly increased survival rates in treated mice compared to controls.
• Validation of a demand-driven molecular design framework for active toxin neutralization.

Conclusions:

• The developed biomimetic system offers an active, on-demand detoxification approach for diquat poisoning.
• Integration of targeted delivery, ROS scavenging, and antioxidant pathway modulation provides a synergistic therapeutic effect.
• This strategy represents a significant advancement over passive detoxification methods, bridging biomaterials engineering and redox biology.