Anti‐Acidification and Immune Regulation by Nano‐Ceria‐Loaded Mg–Al Layered Double Hydroxide for Rheumatoid Arthritis Therapy

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease featuring an abnormal immune microenvironment and resultant accumulation of hydrogen ions (H+) produced by activated osteoclasts (OCs). Currently, clinic RA therapy can hardly achieve sustained or efficient therapeutic outcomes due to the failures in generating sufficient immune modulation and manipulating the accumulation of H+ that deteriorates bone damage. Herein, a highly effective immune modulatory nanocatalytic platform, nanoceria‐loaded magnesium aluminum layered double hydroxide (LDH‐CeO2), is proposed for enhanced immune modulation based on acid neutralization and metal ion inherent bioactivity. Specifically, the mild alkaline LDH initiates significant M2 repolarization of macrophages triggered by the elevated antioxidation effect of CeO2 via neutralizing excessive H+ in RA microenvironment, thus resulting in the efficient recruitment of regulatory T cell (Treg) and suppressions on T helper 17 cell (Th 17) and plasma cells. Moreover, the osteogenic activity is stimulated by the Mg ion released from LDH, thereby promoting the damaged bone healing. The encouraging therapeutic outcomes in adjuvant‐induced RA model mice demonstrate the high feasibility of such a therapeutic concept, which provides a novel and efficient RA therapeutic modality by the immune modulatory and bone‐repairing effects of inorganic nanocatalytic material.

Selective Tumor Inhibition Effect of Drug-Free Layered Double Hydroxide-Based Films via Responding to Acidic Microenvironment

“…To prevent acidosis, a large amount of lactic acid produced during the glycolytic process is transported to the microenvironment by tumor cells through the monocarboxylate transporter pump, so the microenvironment outside tumor cells is acidic, while the microenvironment outside normal cells is weakly basic. − The difference between the two microenvironments can be exploited to design specific acid-responsive materials for the efficient killing of cancer cells while ensuring the safety for normal cells. Layered double hydroxides (LDHs) are classical layered materials with simple and tunable constituent elements. − The main structure of the laminate consists of an ordered stack of two cationic hydroxides in the form of ortho-octahedrons, which have excellent responsiveness to acidic environment. − Zhang et al synthesized weakly basic LDHNPs to disrupt tumor cell autophagy by depleting and excess acid in tumor cells for cancer immunotherapy. Wang et al prepared LDH loaded with etoposide (VP16) and utilized its acid-responsive properties to continuously release VP16 in tumor tissues for the efficient killing of tumorigenic glioma stem cells.…”

Nanohybrid-Based Redox Homeostasis Perturbators Escaped from Early Lysosomes toward Amplified Sensitization of Tumor Cells and Photothermally Maneuvered Pyroptosis Therapy

“…Layered double hydroxide nanosheets (LDH NSs) are slightly alkaline nanomaterials rich in metal ions. 28,29 With their property of degrading under weak acidic conditions and releasing ions as an ion reservoir, 30,31 the combination of LDH and redox-active NPs holds promise as a new strategy to address the aforementioned issues. First, the ion release of LDH increases lysosomal osmotic pressure, promoting early lysosomal escape.…”