Delivery of small interfering RNA by hydrogen sulfide-releasing nanomotor for the treatment of Parkinson's disease

Small interfering RNA (siRNA) that inhibit the formation of α-synuclein (α-syn) aggregates is considered very promising therapeutic agents for the treatment of Parkinson's disease (PD). However, the low stability and the difficulty in crossing the blood-brain barrier (BBB) of free siRNA has severely limited their therapeutic effects. Here, we developed an H2S donor nanomotor that can encapsulate siRNA, which can both protect the activity of siRNA and help siRNA to be effectively targeted to the mitochondria of damaged neuronal cells, in order to promote the effective therapeutic effect of siRNA for PD. Specifically, the cysteine monomer-modified polyethylene glycol (PEG-Cys) and the amphiphilic ionic monomer 2-methacryloyloxyethylphosphorylcholine (MPC) that can effectively penetrate the BBB, were selected to form a polymer protective layer on the surface of siRNA in a free-radical polymerization reaction, to construct the H2S donor nanomotor encapsulating siRNA (PCM@siRNA). Among them, MPC can help PCM@siRNA to break through the BBB by interacting with nicotinic acetylcholine receptor or choline transporter on the surface of cerebrovascular endothelial cells, while PEG-Cys can undergo chemotactic effect by specifically recognizing 3-thiopyruvate thioltransferase and thus achieve effective targeting of damaged mitochondria in neuronal cells. PCM@siRNA that reached neuronal cells can not only be utilized to play the role of silencing the α-syn gene to inhibit the formation of α-syn aggregates by siRNA, but also to degrade the formed α-syn aggregates by using the H2S produced by its chemotaxis process to achieve an effective treatment for PD. This therapeutic modality, which can simultaneously inhibit the formation of α-syn aggregates and promote their degradation, has the therapeutic potential to reverse the pathological state of α-syn, which is important for the treatment of PD. [Display omitted] •This nanomotor can achieve controlled release of H2S, effective penetration of BBB and targeting to damaged mitochondria.•By simultaneously regulating the synthesis and degradation of α-syn aggregates, the removal of α-syn is maximized.•The first report of siRNA delivery using nanomotors.