An Acidosis-Activatable Nanocomposite for Synergistic Microenvironment Remodeling and Reprogramming of...

Area of Science:

• Biomedical Engineering
• Immunology
• Nanotechnology

Background:

• Rheumatoid arthritis (RA) immunotherapy is limited by its pathological microenvironment.
• This microenvironment features maladaptive immune crosstalk, sustained M1 macrophage polarization, and disrupted Treg/Th17 balance.
• Acidosis and reactive oxygen species (ROS) worsen inflammatory damage in RA.

Purpose of the Study:

• To develop a bone-targeting nanocomposite, CCZ-AA, for rheumatoid arthritis (RA) treatment.
• To remodel the RA microenvironment and restore immune homeostasis by modulating innate and adaptive immunity.

Main Methods:

• Development of a bone-targeting nanocomposite: CaO2/CeO2@ZIF-8-ALN-AOA (CCZ-AA).
• Investigation of CCZ-AA's dual regulatory effects under acidic conditions: acid neutralization, oxygen generation, enhanced antioxidant activity, and M1-to-M2 macrophage repolarization.
• Assessment of AOA's role in Treg differentiation and stabilization of M2 polarization, forming a Treg-M2 regulatory loop.
• Evaluation of CCZ-AA in a collagen-induced arthritis (CIA) mouse model.

Main Results:

• CCZ-AA effectively neutralizes excess H+, alleviates acidosis, generates oxygen, and enhances CeO2 antioxidant activity.
• CCZ-AA promotes M1-to-M2 macrophage repolarization and facilitates Treg differentiation, rebalancing the Treg/Th17 axis.
• CCZ-AA establishes a reciprocal Treg-M2 regulatory loop, stabilizing M2 polarization.
• In a CIA mouse model, CCZ-AA significantly increased Treg levels and reduced joint destruction.

Conclusions:

• CCZ-AA shows potential as an immunoregulatory strategy for RA by reprogramming the inflammatory microenvironment.
• The nanocomposite restores immune equilibrium through comodulating innate and adaptive immunity.
• CCZ-AA offers a promising therapeutic approach for rheumatoid arthritis by targeting its underlying immune dysregulation.