Mucoadhesive Peptide‐Catalase Self‐Assembled Nano‐Formulation for Effective Treatment of Mucosal Inflammatory Diseases

ABSTRACT Mucosa, a vital interface between the body and external environment, often suffers from reactive oxygen burden within its microenvironment, leading to various mucosal inflammatory diseases. Drug delivery directly to inflamed mucosal regions offers a promising therapeutic approach, yet efficacy is compromised by inherent physiological clearance mechanisms. Herein, we developed a covalent mucoadhesive nanoantioxidant self‐assembled by a cysteine‐modified short peptide (CR ₈ L ₁₀ ) and catalase (CAT) for the treatment of mucosal inflammatory diseases. The obtained CR ₈ L ₁₀ @CAT nanocomplexes with a cysteine‐decorated surface enable robust mucoadhesion by forming dynamic disulfide bonds with mucin‐rich mucosa, leading to significantly enhanced CAT retention. Upon intravesical instillation, CR ₈ L ₁₀ @CAT with improved urine‐resistant bladder retention, could be used to treat hard‐to‐manage interstitial cystitis/bladder pain syndrome (IC/BPS). Notably, intravesically administered CR ₈ L ₁₀ @CAT effectively eliminated excessive reactive oxygen species (ROS) in the bladder mucosa, thereby inhibiting pro‐inflammatory responses, restoring urothelial integrity, and alleviating pain and voiding dysfunction, demonstrating significantly better analgesic effects and superior functional improvement than clinically used intravesical agents. Additionally, inhalation of the mucoadhesive CR ₈ L ₁₀ @CAT nanoantioxidant also showed enhanced pulmonary retention to effectively mitigate ROS‐associated inflammation in treating acute lung injury (ALI). This mucoadhesive CR ₈ L ₁₀ @CAT nanoantioxidant represents an effective therapeutic strategy to manage different mucosal inflammatory diseases, holding great promise for clinical translation.