Nucleus Pulposus‐Targeting Nanocarriers Facilitate Mirna‐Based Therapeutics for Intervertebral Disc Degeneration

Chen, Zhonghui; Liao, Zhong; Liu, Ming; Lin, Fengfei; Chen, Shunyou; Wang, Geng; Zheng, Zhong; Liu, Boling; Li, Chaoxiong; Wang, Zheqiang; Chen, Tianlai; Huang, Hongzhe; Liao, Qi; Cui, Weiliang

doi:10.1002/adhm.202301337

Cited by 7 publications

(2 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The staining procedures included SO-fast green or HE staining. Two blinded observers assessed cellularity and morphology using a pre-established grading scale [ 58 ].…”

Section: Methodsmentioning

confidence: 99%

Silencing circATXN1 in Aging Nucleus Pulposus Cell Alleviates Intervertebral Disc Degeneration via Correcting Progerin Mislocalization

Yu,

Zhao,

Cheng

et al. 2024

Research

View full text Add to dashboard Cite

Circular RNAs (circRNAs) play a critical regulatory role in degenerative diseases; however, their functions and therapeutic applications in intervertebral disc degeneration (IVDD) have not been explored. Here, we identified that a novel circATXN1 highly accumulates in aging nucleus pulposus cells (NPCs) accountable for IVDD. CircATXN1 accelerates cellular senescence, disrupts extracellular matrix organization, and inhibits mitochondrial respiration. Mechanistically, circATXN1, regulated by heterogeneous nuclear ribonucleoprotein A2B1-mediated splicing circularization, promotes progerin translocation from the cell nucleus to the cytoplasm and inhibits the expression of insulin-like growth factor 1 receptor (IGF-1R). To demonstrate the therapeutic potential of circATXN1, siRNA targeting the backsplice junction of circATNX1 was screened and delivered by tetrahedral framework nucleic acids (tFNAs) due to their unique compositional and tetrahedral structural features. Our siRNA delivery system demonstrates superior abilities to transfect aging cells, clear intracellular ROS, and enhanced biological safety. Using siRNA–tFNAs to silence circATXN1, aging NPCs exhibit reduced mislocalization of progerin in the cytoplasm and up-regulation of IGF-1R, thereby demonstrating a rejuvenated cellular phenotype and improved mitochondrial function. In vivo, administering an aging cell-adapted siRNA nucleic acid framework delivery system to progerin pathologically expressed premature aging mice (zmpste24 −/− ) can ameliorate the cellular matrix in the nucleus pulposus tissue, effectively delaying IVDD. This study not only identified circATXN1 functioning as a cell senescence promoter in IVDD for the first time, but also successfully demonstrated its therapeutic potential via a tFNA-based siRNA delivery strategy.

show abstract

“…The staining procedures included SO-fast green or HE staining. Two blinded observers assessed cellularity and morphology using a pre-established grading scale [ 58 ].…”

Section: Methodsmentioning

confidence: 99%

Silencing circATXN1 in Aging Nucleus Pulposus Cell Alleviates Intervertebral Disc Degeneration via Correcting Progerin Mislocalization

Yu,

Zhao,

Cheng

et al. 2024

Research

View full text Add to dashboard Cite

show abstract

“…Delivery of miR-22-3p inhibitors and mimics through nanoparticles synthesized in the IVDD model alleviated and exacerbated IVDD, respectively. The nanocarriers enhanced miR-22-3p translocation to myeloid NP cells, which led to in vivo inhibition of miR-22-3p, thereby facilitating the development of miRNA-specific drugs for IVDD (Chen et al 2023a). miR-141 promotes IVDD by targeting and depleting SIRT1, a negative regulator of the NF-κB pathway (Ji et al 2018).…”

Section: Exploring Avenues For Enhancing Cell Survival Through Sirtui...mentioning

confidence: 99%

Sirtuins in intervertebral disc degeneration: current understanding

Shen,

Lan,

et al. 2024

Mol Med

View full text Add to dashboard Cite

Background Intervertebral disc degeneration (IVDD) is one of the etiologic factors of degenerative spinal diseases, which can lead to a variety of pathological spinal conditions such as disc herniation, spinal stenosis, and scoliosis. IVDD is a leading cause of lower back pain, the prevalence of which increases with age. Recently, Sirtuins/SIRTs and their related activators have received attention for their activity in the treatment of IVDD. In this paper, a comprehensive systematic review of the literature on the role of SIRTs and their activators on IVDD in recent years is presented. The molecular pathways involved in the regulation of IVDD by SIRTs are summarized, and the effects of SIRTs on senescence, inflammatory responses, oxidative stress, and mitochondrial dysfunction in myeloid cells are discussed with a view to suggesting possible solutions for the current treatment of IVDD. Purpose This paper focuses on the molecular mechanisms by which SIRTs and their activators act on IVDD. Methods A literature search was conducted in Pubmed and Web of Science databases over a 13-year period from 2011 to 2024 for the terms “SIRT”, “Sirtuin”, “IVDD”, “IDD”, “IVD”, “NP”, “Intervertebral disc degeneration”, “Intervertebral disc” and “Nucleus pulposus”. Results According to the results, SIRTs and a large number of activators showed positive effects against IVDD.SIRTs modulate autophagy, myeloid apoptosis, oxidative stress and extracellular matrix degradation. In addition, they attenuate inflammatory factor-induced disc damage and maintain homeostasis during disc degeneration. Several clinical studies have reported the protective effects of some SIRTs activators (e.g., resveratrol, melatonin, honokiol, and 1,4-dihydropyridine) against IVDD. Conclusion The fact that SIRTs and their activators play a hundred different roles in IVDD helps to better understand their potential to develop further treatments for IVDD. Novelty This review summarizes current information on the mechanisms of action of SIRTs in IVDD and the challenges and limitations of translating their basic research into therapy.

show abstract

Cartilage Endplate‐Targeted Engineered Exosome Releasing and Acid Neutralizing Hydrogel Reverses Intervertebral Disc Degeneration

Zhan,

Cui,

Zhang

et al. 2024

Adv Healthcare Materials

View full text Add to dashboard Cite

Cartilage endplate cell (CEPC) and nucleus pulposus cell (NPC) inflammation are critical factors that contribute to intervertebral disc degeneration (IVDD). Recent evidence indicated that iron ion influx, reactive oxygen species (ROS), and the cGAS‐STING pathway are involved in CEPC inflammatory degeneration. Moreover, cytokines produced by degenerating CEPCs and lactic acid accumulation within the microenvironment significantly contribute to NPC inflammation. Consequently, simultaneous alleviation of CEPC inflammation and correction of the acidic microenvironment are anticipated to reverse IVDD. Herein, CEPC‐targeted engineered exosomes loaded with salvianolic acid A are incorporated into a CaCO3/chitosan hydrogel, forming a composite gel, CAP‐sEXOs@Gel. Notably, CAP‐sEXOs@Gel shows long local retention, realizes the slow release of CAP‐sEXOs and specific uptake by CEPCs. After uptake by CEPCs, CAP‐sEXOs reduce intracellular iron ion and ROS by inhibiting hypoxia‐inducible factor‐2α (HIF‐2α)/TfR1 expression. Iron ion influx and ROS inhibition contribute to the maintenance of normal mitochondrial function and reduced mtDNA leakage, suppresing the cGAS‐STING pathway. Additionally, the CaCO3 component of CAP‐sEXOs@Gel neutralizes H+, thereby alleviating NPC inflammation. Collectively, this novel composite hydrogel demonstrates the ability to concurrently inhibit CEPC and NPC inflammation, thereby presenting a promising therapeutic approach for IVDD.

show abstract

Nucleus Pulposus‐Targeting Nanocarriers Facilitate Mirna‐Based Therapeutics for Intervertebral Disc Degeneration

Cited by 7 publications

References 48 publications

Silencing circATXN1 in Aging Nucleus Pulposus Cell Alleviates Intervertebral Disc Degeneration via Correcting Progerin Mislocalization

Silencing circATXN1 in Aging Nucleus Pulposus Cell Alleviates Intervertebral Disc Degeneration via Correcting Progerin Mislocalization

Sirtuins in intervertebral disc degeneration: current understanding

Cartilage Endplate‐Targeted Engineered Exosome Releasing and Acid Neutralizing Hydrogel Reverses Intervertebral Disc Degeneration

Contact Info

Product

Resources

About