Functionalized Nanozyme Microcapsules Targeting Deafness Prevention via Mitochondrial Homeostasis Remodeling

Abstract Mitochondrial dysfunction, which is the primary mechanism underlying cisplatin‐induced hearing loss, can potentially be mitigated by modulating the redox balance and reprogramming the energy metabolism to remodel mitochondrial homeostasis. Herein, N ‐acetyl‐ l ‐cysteine–derived carbonized polymer dots (NAC CPDs) are embedded into manganese porphyrin–doped metal–organic frameworks and encapsulated using a polydopamine (PDA) coating and gelatin methacryloyl (GelMA) hydrogel to afford functionalized nanozyme microcapsules. Owing to their injectability and adhesion properties, these microcapsules exhibit the advantages of prolonged retention in the middle ear and sustained release in the inner ear. The synergy between the manganese porphyrin and polymer dots results in excellent antioxidant properties. The developed nanozymes activate the PI3K‐AKT pathway, reprogramming the energy supply mechanism, and inhibiting the oligomerization of BAX in mitochondria to prevent the leakage of mitochondrial DNA and cytochrome c. Therapeutic efficacy and related mechanisms are validated in vivo. Thus, this study on mitochondrial homeostasis remodeling by nanozyme microcapsules opens a new chapter in the treatment of hearing loss.