A STIR nucleic acid drug delivery system for stirring phenotypic switch of microglia in Parkinson’s disease treatments

Neuroinflammation is one of the three important pathological features in neurodegenerative diseases including Parkinson’s disease (PD). The regulation of neuroinflammation can reduce the severity of neurological damage to alleviate diseases. Numerous studies have shown that the phenotype switch of microglia is tightly associated with the nuclear factor κB (NF-κB)-mediated inflammatory pathway. Therefore, the small interfering RNA (siRNA) therapy for downregulating the expression of NF-κB, provides a promising therapeutic strategy for Parkinson’s disease treatments. Considering the brain delivery challenges of siRNA, a sequential targeting inflammation regulation (STIR) delivery system based on poly(amino acid)s is developed to improve the therapeutic effects of Parkinson’s disease treatments. The STIR system sequentially targets the blood–brain barrier and the microglia to enhance the effective concentration of siRNA in the targeted microglia. The results demonstrate that the STIR nanoparticles can transform microglial phenotypes and regulate brain inflammation, thus achieving neuronal recovery and abnormal aggregation of α-synuclein protein (α-syn) reduction in the treatment of Parkinson’s disease. Herein, this STIR delivery system provides a promising therapeutic platform in PD treatments and has great potential for other neurodegenerative diseases’ therapies.