A Redox Homeostasis Modulatory Hydrogel with GLRX3⁺ Extracellular Vesicles Attenuates Disc Degeneration by Suppressing Nucleus Pulposus Cell Senescence

Abstract

Characterized by nucleus pulposus (NP) cell senescence and extracellular matrix (ECM) degradation, disc degeneration is a common pathology for various degenerative spinal disorders. To date, effective treatments for disc degeneration are absent. Here, we found that Glutaredoxin3 (GLRX3) is an important redox-regulating molecule associated with NP cell senescence and disc degeneration. Using a hypoxic preconditioning method, we developed GLRX3+ mesenchymal stem cell-derived extracellular vehicles (EVs-GLRX3), which enhanced the cellular antioxidant defense, thus preventing reactive oxygen species (ROS) accumulation and senescence cascade expansion in vitro. Further, a disc tissue-like biopolymer-based supramolecular hydrogel, which was injectable, degradable, and ROS-responsive, was proposed to deliver EVs-GLRX3 for treating disc degeneration. Using a rat model of disc degeneration, we demonstrated that the EVs-GLRX3-loaded hydrogel attenuated mitochondrial damage, alleviated the NP senescence state, and restored ECM deposition by modulating the redox homeostasis. Our findings suggested that modulation of redox homeostasis in the disc can rejuvenate NP cell senescence and thus attenuate disc degeneration.

Core–Shell Structured Nanozyme with PDA-Mediated Enhanced Antioxidant Efficiency to Treat Early Intervertebral Disc Degeneration

“…ROS play critical roles in the pathogenesis of IDD by causing OS damage and activating crucial signals related to inflammatory response, senescence, and apoptosis. , Here, we designed a core–shell structured PDA@CNO nanoparticle with multiple enzyme-like activities (Figure A), expecting to effectively mitigate the ROS level in the microenvironment of degenerated IVD.…”

Artificial Homeostasis Systems Based on Feedback Reaction Networks: Design Principles and Future Promises

“…[117] Today, various forms of homeostasis have been achieved with nanomaterial-based systems, including redox state, energy metabolism, ion balance, and cell-cell interaction, in order to treat various diseases, maintaining cell oxidative stress, emerging artificial enzymatic activities, sensing, and others. [118] In fact, attaining minimalistic synthetic homeostasis systems likely helps us understand the various biological pathways such as glucose homeostasis, thyroid regulatory homeostasis, and others, which is expected to open a scope beyond the present-day proof-of-concept in developing biotechnology-based devices for diagnosis and health care. Thus, exciting developments can be foreseen in the near future with the advancement towards life-like material systems for a broader spectrum of functionalities.…”

Mesenchymal stem cell‐derived extracellular vesicles: Recent therapeutics and targeted drug delivery advances

“…Studies indicate that MSC‐EVs have shown substantial therapeutic potential in various disease conditions without any modification (Chen et al., 2023, Rani et al., 2015, Yang et al., 2023, Zeng et al., 2022). However, these EVs are often complemented with specific formulations, adhesives, or hydrogels to increase their intrinsic therapeutic efficiencies (Liu et al., 2023, Wang et al., 2023). For designing efficient EV‐based therapeutics, endogenous encapsulation of target molecules within the EV lumen and their exogenous addition are currently two main drug‐loading techniques (Figure 2).…”