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

Wenjing Wang; Zinan Zhao; Ziqiang Zhang; Zhuolin Wu; Yao Zhang; Keheng Wang; Min Dai; Chun Mao; Mimi Wan

doi:10.1016/j.jconrel.2024.11.069

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

J Control Release. 2024 Nov 30:377:648-660. doi: 10.1016/j.jconrel.2024.11.069. Online ahead of print.

Authors

Wenjing Wang¹, Zinan Zhao², Ziqiang Zhang², Zhuolin Wu², Yao Zhang², Keheng Wang², Min Dai², Chun Mao³, Mimi Wan⁴

Affiliations

¹ National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China; Institute for Life and Health, Nanjing Drum Tower Hospital, Nanjing Normal University, Nanjing 210023, China.
² National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
³ National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China; Institute for Life and Health, Nanjing Drum Tower Hospital, Nanjing Normal University, Nanjing 210023, China. Electronic address: maochun@njnu.edu.cn.
⁴ National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China; Institute for Life and Health, Nanjing Drum Tower Hospital, Nanjing Normal University, Nanjing 210023, China. Electronic address: wanmimi@njnu.edu.cn.

PMID: 39613107
DOI: 10.1016/j.jconrel.2024.11.069

Abstract

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.

Keywords: H(2)S donor; Nanomotor; Parkinson's disease; Synergistic therapy; siRNA.