Redox Nanomedicine Cures Chronic Kidney Disease (CKD) by Mitochondrial Reconditioning

Abstract

Targeting reactive oxygen species (ROS) while maintaining cellular redox signaling is crucial in the development of redox medicine for the therapeutic benefit as the origin of several prevailing diseases including chronic kidney disease (CKD) is linked to ROS imbalance and associated mitochondrial dysfunction. Here, we have shown that an indigenously developed nanomedicine comprising of Mn3O4 nanoparticles duly functionalized by biocompatible ligand citrate (C-Mn3O4 NPs) can maintain cellular redox balance in an animal model. We developed a cisplatin-induced CKD model in C57BL/6j mice where severe mitochondrial dysfunction resulting in oxidative distress lead to the pathogenesis. Four weeks of treatment with C-Mn3O4 NPs restored renal function, preserved normal kidney architecture, ameliorated overexpression of pro-inflammatory cytokines, and arrested glomerulosclerosis and interstitial fibrosis in CKD mice. A detailed study involving human embryonic kidney (HEK 293) cells and isolated mitochondria from experimental animals revealed that the molecular mechanism behind the pharmacological action of the nanomedicine involves protection of structural and functional integrity of mitochondria from oxidative damage, the subsequent reduction in intracellular ROS, and maintenance of cellular redox homeostasis. To the best of our knowledge, such studies that efficiently treated a multifaceted disease like CKD using a biocompatible redox nanomedicine are sparse in the literature. Successful clinical translation of this nanomedicine may open a new avenue in redox-mediated therapeutics of several other diseases (e.g., diabetic nephropathy, neurodegeneration, and cardiovascular disease) where oxidative distress plays a central role in pathogenesis.

Redox nanomedicine ameliorates chronic kidney disease (CKD) by mitochondrial reconditioning in mice

“…All essential data are provided in the manuscript. The datasets generated and analyzed during this study to support the findings are available in a DOI-minting online open access repository, figshare, with the identifier (10.6084/m9.figshare.14995122) 97 . Any remaining information can be obtained from the corresponding author upon reasonable request.…”

The applications of functional materials-based nano-formulations in the prevention, diagnosis and treatment of chronic inflammation-related diseases

“…In addition, subspherical Mn 3 O 4 NPs of 5.58 ± 2.42 nm moderately functionalized with the biocompatible ligand citric acid may have great potential in CKD treatment. This redox nanomedicine can regulate redox homeostasis, downregulate pro-inflammatory cytokines, and attenuate renal injury with tubular intestinal fibrosis by synchronizing the causal relationship between mitochondrial protection and ROS scavenging (Adhikari et al, 2021). Few published articles have utilized redox modulation approaches to treat chronic diseases, and this field remains to be continually explored.…”

Functionalized Mn3O4 Nanosheets with Photothermal, Photodynamic, and Oxidase‐Like Activities Triggered by Low‐Powered Near‐Infrared Light for Synergetic Combating Multidrug‐Resistant Bacterial Infections

“…[30] Inspired by these facts mentioned above, we engineered a new kind of indocyanine green (ICG)-functionalized hexagonal Mn 3 O 4 nanosheets (Mn 3 O 4 HNSs@ICG) with photothermal, photodynamic, and oxidase (OXD)-like activities and applied them in synergetic combating MDR bacterial infections (Scheme 1). Mn 3 O 4 HNSs were chosen for the following rea-sons: i) manganese oxides generally have wide absorption from UV to NIR region and thus can convert light energy into hyperpyrexia, [31] which are promising photothermal agents with low cost; ii) the biocompatibility of Mn 3 O 4 nanoparticles has been demonstrated, including good blood compatibility, no effect on glucose metabolism and lipid level in mice, no reproductive damage as well as undetectable toxicity to organs in mice; [32][33][34][35] iii) both Mn 3+ and Mn 2+ ions are involved in Mn 3 O 4 HNSs, which is favorable for electron transfer in the Fenton-like reaction and thus promote the generation of ROS for treatment. ICG was further modified on the surface of Mn 3 O 4 HNSs since it is the only NIR agent and photosensitizer (𝜆 max = 780 nm) approved by the U.S. Food and Drug Administration (FDA) for clinical use.…”