Self‐Catalytic Small Interfering RNA Nanocarriers for Synergistic Treatment of Neurodegenerative Diseases

Abstract Gene therapy has shown great potential for neurodegenerative diseases with complex pathology. However, its therapeutic effect is limited due to the delivery barriers and its own single function. Herein, self‐catalytic small interfering RNA (siRNA) nanocarriers (S/Ce‐PABMS) are developed to catalyze delivery process and treatment process for synergistic treatment of neurodegenerative diseases. On the one hand, the rough surface of the S/Ce‐PABMS mediated by ceria (CeO₂) nanozymes can catalyze cellular uptake in the delivery process, so that S/Ce‐PABMS with acetylcholine analogs penetrate the blood–brain barrier and enter neurons more effectively. On the other hand, the CeO₂ nanozymes can catalyze the treatment process by scavenging excess reactive oxygen species, and cooperate with siRNA‐targeting SNCA to decrease the α‐synuclein (α‐syn) aggregation and alleviate the Parkinsonian pathology. Moreover, the S/Ce‐PABMS treatment reduces the number of activated microglia and regulates the release of inflammatory cytokine, thereby relieving neuroinflammation. After treatment with S/Ce‐PABMS, dyskinesia in Parkinson's disease model mice is significantly alleviated. The finding shows that the self‐catalytic nanocarriers, S/Ce‐PABMS, have great potential in the treatment of neurodegenerative diseases.