Mitochondria-targeted SkQ1 nanoparticles for dry eye disease: Inhibiting NLRP3 inflammasome activation by preventing mitochondrial DNA oxidation

Baoshan Huang; Na Zhang; Xinying Qiu; Rui Zeng; Shuimiao Wang; Mengxia Hua; Qing Li; Kaihui Nan; Sen Lin

doi:10.1016/j.jconrel.2023.11.021

Mitochondria-targeted SkQ1 nanoparticles for dry eye disease: Inhibiting NLRP3 inflammasome activation by preventing mitochondrial DNA oxidation

J Control Release. 2024 Jan:365:1-15. doi: 10.1016/j.jconrel.2023.11.021. Epub 2023 Nov 18.

Authors

Baoshan Huang¹, Na Zhang², Xinying Qiu³, Rui Zeng³, Shuimiao Wang³, Mengxia Hua³, Qing Li⁴, Kaihui Nan⁵, Sen Lin⁶

Affiliations

¹ National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China; School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325027, China.
² National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China; First Affiliated Hospital of Northwestern University, Shaanxi Institute of Ophthalmology, Shaanxi Key Laboratory of Ophthalmology, Xi'an 710002, China.
³ National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China.
⁴ Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, China. Electronic address: liqing@wiucas.ac.cn.
⁵ National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China; School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325027, China. Electronic address: nankh@wmu.edu.cn.
⁶ National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China; Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, China; School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325027, China. Electronic address: lin_sen@wmu.edu.cn.

PMID: 37972763
DOI: 10.1016/j.jconrel.2023.11.021

Abstract

Dry eye disease (DED) is a multifactorial ocular surface disorder mutually promoted by reactive oxygen species (ROS) and ocular surface inflammation. NLRP3 is the key regulator for inducing ocular surface inflammation in DED. However, the mechanism by which ROS influences the bio-effects of NLRP3, and the consequent development of DED, largely remains elusive. In the present study, we uncovered that robust ROS can oxidate mitochondrial DNA (ox-mtDNA) along with loss of mitochondria compaction causing the cytosolic release of ox-mtDNA and subsequent co-localization with cytosolic NLRP3, which can promote the activation of NLRP3 inflammasome and stimulate NLRP3-mediated inflammation. Visomitin (also known as SkQ1), a mitochondria-targeted anti-oxidant, could reverse such a process by in situ scavenging of mitochondrial ROS. To effectively deliver SkQ1, we further developed a novel mitochondria-targeted SkQ1 nanoparticle (SkQ1 NP) using a charge-driven self-assembly strategy. Compared with free SkQ1, SkQ1 NPs exhibited significantly higher cytosolic- and mitochondrial-ROS scavenging activity (1.7 and 1.9 times compared to levels of the free SkQ1 group), thus exerting a better in vitro protective effect against H₂O₂-induced cell death in human corneal epithelial cells (HCECs). After topical administration, SkQ1 NPs significantly reduced in vivo mtDNA oxidation, while suppressing the expressions of NLRP3, Caspase-1, and IL-1β, which consequently resulted in better therapeutic effects against DED. Results suggested that by efficiently scavenging mitochondrial ROS, SkQ1 NPs could in situ inhibit DED-induced mtDNA oxidation, thus blocking the interaction of ox-mtDNA and NLRP3; this, in turn, suppressed NLRP3 inflammasome activation and NLRP3-mediated inflammatory signaling. Results suggested that SkQ1 NPs have great potential as a new treatment for DED.

Keywords: Dry eye disease; Mitochondria-specific antioxidants; Mitochondrial DNA; NLRP3 inflammasome; SkQ1 nanoparticle.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA, Mitochondrial
Dry Eye Syndromes*
Humans
Hydrogen Peroxide / metabolism
Inflammasomes / metabolism
Inflammasomes / pharmacology
Inflammation / metabolism
Mitochondria
NLR Family, Pyrin Domain-Containing 3 Protein
Nanoparticles*
Reactive Oxygen Species / metabolism

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
DNA, Mitochondrial
Reactive Oxygen Species
Hydrogen Peroxide