Aug 2026· Advancement of science· 0 citations· 57 references
Medicine
TL;DR
The gene-edited mFD-PEVs reprogram redox homeostasis in NPCs, regulate ferroptosis, and promote intervertebral disc regeneration.
Abstract
ABSTRACT Intervertebral disc degeneration (IDD) is driven by ferroptosis of nucleus pulposus cells (NPCs) as a core pathological mechanism. Nucleus pulposus progenitor cells (NPPCs), exhibiting stem cell‐like properties, yield extracellular vesicles (PEVs) with high affinity for NPCs and enable targeted phenotypic regulation. However, natural PEVs possess limited bioactivity. Therefore, we constructed engineered mFD‐PEVs modified with FTH1 and DAB2. In vitro experiments demonstrated that mFD‐PEVs efficiently deliver FTH1, maintained SLC7A11/GPX4‐associated redox defense, suppress NPCs oxidative stress, and attenuate ferroptosis. Furthermore, in vivo studies confirmed the potent therapeutic efficacy of mFD‐PEVs in promoting intervertebral disc regeneration. Transcriptomic analysis further revealed that mFD‐PEVs predominantly modulate molecular pathways associated with ferroptosis and oxidative stress. In summary, the gene‐edited mFD‐PEVs reprogram redox homeostasis in NPCs, regulate ferroptosis, and promote intervertebral disc regeneration.
Intervertebral disc degeneration (IVDD) arises from disrupted metabolism and redox imbalance, severely impairing nucleus pulposus (NP) cells' ability to repair the extracellular matrix (ECM). The early stage of IVDD is marked by excessive oxidative stress, lipid peroxidation, iron dysregulation and sustained catabolic enzyme activity, while late-stage cellular aging ultimately renders NP cells highly susceptible to iron-dependent cell death. To address these stage-specific challenges, we developed a pathology-adaptive self-assembling hydrogel that exploits dynamically varying catabolic enzyme activity to trigger on-demand delivery of antioxidant molecules and bioactive extracellular vesicles. Upon recognition of pathologically elevated MMP13, the hydrogel undergoes site-specific structural disruption, thereby enabling spatiotemporally controlled exosome release. The hydrogel complex stabilizes redox balance by boosting intracellular glutathione, mitigating lipid peroxidation and restoring iron homeostasis. Furthermore, it activates PI3K-Akt signaling and reinstates key anti-ferroptosis proteins. Simultaneously, it promotes the synthesis of proteoglycans and type II collagen, collectively rebuilding the ECM niche. The combined effect of restored redox balance and regenerative signaling leads to significant structural and functional recovery of the damaged disc, as strongly evidenced in vivo animal studies. Overall, this spatiotemporal-adaptive platform establishes a multifaceted strategy for regenerative engineering, offering a promising option for complex degenerative diseases.
Zhan Gao, Gan Lyu, Qiwei Zhou et al.· Advances in Materials· 0 citations
Intervertebral disc (IVD) degeneration (IVDD) is a major cause of lower back pain, characterized by oxidative stress accumulation and impaired autophagic flux leading to nucleus pulposus cell (NPC) degeneration. Transcription factor E3 (TFE3) is crucial in autophagy regulation. MXene, a nanomaterial known for its antioxidant capability, exhibits satisfactory therapeutic effects in various diseases. This study investigates the role of TFE3 and evaluates the therapeutic potential of Ti3C2 MXene-based nanocomposites in IVDD. The Ti3C2@PtAu@TFE3 nanocomposite was designed, with properties of anti-oxidation and pro-autophagic flux, alleviated extracellular matrix (ECM) degradation and senescence in NPCs. In a needle puncture-induced IVDD rat model, intra-disc injection of Ti3C2@PtAu@TFE3 alleviated structural deterioration and prevented ECM destruction. This study highlights the critical role of TFE3 in IVDD pathogenesis and demonstrates the potential application of Ti3C2@PtAu@TFE3 against IVDD.
Jianle Wang, Tianyou Gao, Yingfeng Su et al.· International Journal of Bio...· 0 citations
ABSTRACT Osteoarthritis (OA) is a progressive and disabling joint disease driven by oxidative stress, chondrocyte senescence and extracellular matrix (ECM) degradation, yet lacks effective disease‐modifying treatments. In this study, we identified miR‐197‐3p as a previously unrecognized, cartilage‐protective miRNA significantly downregulated in both aged and osteoarthritic cartilage. Functional studies revealed that miR‐197‐3p restores ECM anabolism, suppresses senescence and directly targets G3BP1, a stress granule protein linked to redox imbalance and inflammatory signaling. To enable effective intra‐articular delivery, we engineered a multifunctional microsphere platform (miR/PBNP@Gel) by co‐encapsulating miR‐197‐3p and ultrasmall Prussian blue nanozymes (PBNPs) into GelMA hydrogel microspheres. This composite design synergistically enhances miRNA stability, facilitates cellular internalization and provides continuous reactive oxygen species (ROS) scavenging to protect mitochondrial function. miR/PBNP@Gel reversed mitochondrial dysfunction and senescence in OA chondrocytes, while promoting cartilage repair and joint function in vivo. Metabolomic profiling further revealed reprogramming of TCA cycle and antioxidant pathways. This work established miR‐197‐3p as a novel therapeutic regulator in OA and introduced a bioinstructive, injectable, and cell‐free strategy that integrates miRNA therapy and redox modulation for disease modification and cartilage regeneration.
Xuejie Cai, Zehui Lv, Chen Zhang et al.· Advancement of science· 0 citations
ABSTRACT Intervertebral disc degeneration (IDD) is a leading cause of low back pain with incompletely understood mechanisms. Although autophagy dysfunction is a documented contributor to IDD, the precise pathobiological role of chaperone‐mediated autophagy (CMA) remains poorly understood. Here, we demonstrate that CMA activity is downregulated in nucleus pulposus cells (NPCs) from IDD patients and IL‐1β‐induced rat intervertebral disc cell models, causing cytoplasmic accumulation of a novel CMA substrate, Midnolin (MIDN). Accumulated MIDN bypasses the ubiquitin‐proteasome system and directly binds to Tuberous Sclerosis Complex 2 (TSC2), mediating its degradation. TSC2 loss relieves mechanistic target of rapamycin complex 1 (mTORC1) inhibition, resulting in mTORC1 hyperactivation, which drives cellular senescence, senescence‐associated secretory phenotype (SASP), and extracellular matrix (ECM) degradation in NPCs. In vitro and in a rat caudal needle puncture model, MIDN knockdown (shRNA), CMA activation (LAMP2A overexpression), or mTORC1 inhibition (Rapamycin) significantly attenuated IL‐1β or MIDN overexpression‐induced senescence and disc degeneration. Our findings reveal an “Impaired CMA–MIDN accumulation–TSC2 degradation–mTORC1 activation” axis central to IDD pathogenesis, offering potential therapeutic targets.
Xianglong Chen, Hai-Yang Gao, Wang Wu et al.· Advancement of science· 0 citations
Intervertebral disc degeneration (IDD) is a major cause of low back pain, driven by nucleus pulposus (NP) cell dysfunction, excessive reactive oxygen species (ROS), and chronic inflammation. Current biomaterial-based strategies often fail to simultaneously address oxidative stress and inflammatory signaling in a sustained and synergistic manner. Here, we develop a thermosensitive Pluronic F127-based composite hydrogel co-delivering a tannic acid‑cerium nanozyme and the FPR1 antagonist HCH6-1. The hydrogel undergoes sol-gel transition at body temperature, enabling minimally invasive injection and sustained local release in the intervertebral disc. The cerium nanozyme exerts potent ROS-scavenging activity, effectively reducing intracellular ROS levels and upregulating the antioxidant protein TXNRD1. Meanwhile, HCH6-1 specifically antagonizes FPR1, thereby suppressing cGAS-STING pathway activation and suppressing downstream inflammatory cascades. Beyond direct anti-inflammatory effects, this system significantly enhances mitophagy activity in NP cells, facilitating the clearance of dysfunctional mitochondria and restoring autophagic flux. Collectively, in vitro and in vivo evidence confirms that this dual-functional hydrogel attenuates NP cell inflammation and significantly retards the progression of IDD. Thus, this injectable and biocompatible platform offers a synergistic strategy that couples nanozyme-mediated antioxidant therapy with targeted FPR1 blockade, holding substantial promise for intervertebral disc repair.
Zhiwei Liao, Guoqiang Yin, Jingpei Liu et al.· Journal of Controlled Releas...· 0 citations
ABSTRACT Intervertebral disc degeneration (IVDD) is a major contributor to low back pain, but the immune‐metabolic events that sustain disc inflammation remain poorly defined. Here, we investigated whether disturbed macrophage lipid handling promotes IVDD by coupling cellular senescence to defective efferocytosis. Clinical magnetic resonance imaging and biochemical profiling showed that advanced IVDD was accompanied by increased disc fat fraction and systemic lipid abnormalities. Mendelian randomisation, bulk transcriptomics, machine‐learning modelling and single‐cell RNA sequencing further linked lipid metabolic disturbance to immune remodelling in degenerative discs, and identified TIAM2, SLC44A4, PPT1 and PTGDS as lipid metabolism‐related hub genes associated with IVDD. At the single‐cell level, disc macrophages with low glycerophospholipid metabolism scores showed higher senescence activity, a more inflammatory polarisation state and reduced efferocytosis‐related signatures. Functional studies in bone marrow‐derived macrophages indicated that lipid overload promoted lipid droplet accumulation, lipid peroxidation, impaired lipophagy and cholesterol efflux, activation of the p53/p21 senescence pathway, and reduced apoptotic nucleus pulposus cell clearance. Restoring lipid homeostasis with rosuvastatin enhanced lipophagy, recovered ABCA1/ABCG1‐mediated cholesterol export, attenuated macrophage senescence and inflammatory activation and improved efferocytosis. In a rat needle puncture model, local rosuvastatin delivery alleviated disc structural damage, preserved proteoglycan content, balanced extracellular matrix metabolism and reduced macrophage senescence and inflammatory markers. In conclusion, this study supports macrophage lipid homeostasis as an important regulator of IVDD‐associated immune dysfunction through senescence‐associated impairment of efferocytosis.
Jinyu Wang, Shiyong Ling, Qi Wang et al.· Cell Proliferation· 0 citations
A new method for surgically removing training examples from a model reveals that as datasets grow, the link between what a model learns and what it produces dissolves.
