Abstract
Xerostomia, or dry mouth, manifests as a symptom of hyposalivation. Current clinical management primarily relies on palliative therapies to alleviate symptoms. However, progressive salivary gland damage often leads to irreversible functional loss, severely compromising patients' quality of life. Consequently, there is an urgent need for therapeutics that can promote salivary gland repair and functional recovery. Herein, we developed a novel cerium-based nanozyme delivery system for hyposalivation immunotherapy. Following intravenous injection, the nanosystem preferentially accumulates in mouse submandibular glands, leveraging the reported affinity of its copolymer coating for muscarinic acetylcholine receptors. At the target site, the nanozyme scavenges reactive oxygen species by mimicking superoxide dismutase and catalase activities. This antioxidant action mitigates local inflammation and tissue edema, restores functional gland morphology, and ultimately enhances saliva secretion. Transcriptomic analysis further revealed that the treatment modulates multiple immune-related and inflammatory signaling pathways. Collectively, this cerium nanozyme-based immunomodulatory strategy represents a promising approach for treating hyposalivation and addressing progressive salivary gland injury.