Jul 2026· Journal of Controlled Release· pp.
115192
· 0 citations· 38 references
Medicine
TL;DR
In vitro and in vivo evidence confirms that this dual-functional hydrogel attenuates NP cell inflammation and significantly retards the progression of IDD, offering a synergistic strategy that couples nanozyme-mediated antioxidant therapy with targeted FPR1 blockade, holding substantial promise for intervertebral disc repair.
Abstract
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.
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 leads to significant structural and functional recovery of the damaged disc, as strongly evidenced in vivo animal studies.
Zhan Gao, Gan Lyu, Qiwei Zhou et al.· Advances in Materials· 0 citations
Intervertebral disc degeneration (IDD) is a primary cause of low back pain, characterized by cell loss, extracellular matrix (ECM) degradation, and a harsh microenvironment with excessive oxidative stress, creating an urgent need for regenerative therapies. This study aimed to develop and evaluate a multifunctional injectable hydrogel (Gel@MnO2/GDF6) co-delivering growth differentiation factor 6 (GDF6) for anabolic stimulation and manganese dioxide (MnO2) nanozymes for reactive oxygen species (ROS) scavenging to treat IDD. The MnO2 nanorods and the chitosan-arginine/oxidized dextran-based hydrogel were synthesized and characterized, demonstrating sustained GDF6 release and pH-responsive degradation. In vitro, Gel@MnO2/GDF6 protected nucleus pulposus (NP) cells from H2O2-induced oxidative stress by reducing ROS, upregulating antioxidant enzymes, promoting anabolic ECM metabolism (increasing Aggrecan and Collagen II while decreasing ADAMTS-4 and MMP-13), reducing key inflammatory cytokine expression (TNF-α and IL-6), and activating the Smad pathway. In vivo, intra-discal injection of Gel@MnO2/GDF6 into a rat IDD model significantly attenuated disc degeneration over 12 weeks, as evidenced by improved histological scores, preserved disc height and hydration on radiological and MRI assessments, restoration of ECM protein homeostasis, reduced cellular apoptosis, mitigated inflammatory marker expression, and activated Smad pathway, with these therapeutic effects being superior to those achieved with hydrogels containing only MnO2 or GDF6. Importantly, all tested hydrogel formulations, including Gel@MnO2/GDF6, demonstrated good systemic biocompatibility. These findings collectively demonstrate that the multifunctional Gel@MnO2/GDF6 hydrogel effectively promotes intervertebral disc regeneration by concurrently mitigating oxidative stress and fostering an anabolic, anti-inflammatory microenvironment, validating its potential as a promising therapeutic method for IDD.
Chao Wei, Qin Tang, Yanlin Tan et al.· Free Radical Biology & Medic...· 0 citations
Intervertebral disc degeneration, the leading cause of chronic low back pain, remains incurable with traditional conservative therapies limited to symptomatic alleviation. We present an ECM-mimetic injectable hydrogel (HPTC) synthesized via dynamic crosslinking of hyaluronic acid-phenylboronic acid (HA-PBA) and tannic acid-cerium(III) metal-polyphenol networks (TA-Ce³⁺ MPNs), which faithfully recapitulates native nucleus pulposus ECM to enable functional tissue regeneration. In vitro, HPTC presented broad-spectrum reactive oxygen species scavenging and downregulated pro-inflammatory cytokine expression (TNF-α, IL-1β, IL-6), while upregulating anti-inflammatory markers (IL-4, IL-10). Crucially, Ce³⁺ effectively reduced dissolved oxygen levels (to 105% vs. 115% in control at 15 min), thereby promoting HIF-1α signal expression and mitigating nucleus pulposus cells senescence under H₂O₂-induced oxidative stress. In rat and rabbit intervertebral disc degeneration models, a single, minimally invasive injection of the ECM-mimetic HPTC hydrogel preserved the disc height index and magnetic resonance imaging signal intensity, enhanced aggrecan and collagen II deposition, suppressed inflammatory mediators, and elevated HIF-1α while reducing p21 expression in situ. Transcriptomic analysis further implicated HIF-1α pathways in ECM regeneration. All these findings demonstrate that the HPTC hydrogel leverages metal-polyphenol chemistry within an ECM-inspired framework to synergistically modulate oxygen homeostasis, oxidative stress, and inflammation, offering a bifunctional and biomimetic platform for disc regeneration.
Yifan Wang, Minglang Zou, Junyao Cheng et al.· Journal of Nanobiotechnology· 0 citations
Stroke is a leading global cause of disability and death, with ischemic stroke posing a particularly severe threat. Despite reperfusion therapy, poor outcomes often persist due to oxidative stress, neuroinflammation, and nerve impairment. This study developed an injectable hydrogel based on dual-modified hyaluronic acid for sustained delivery of exosome-cerium oxide nanocomposite (EXO@CeO2), targeting the pathological brain microenvironment after ischemic stroke. In an oxygen-glucose deprivation model, EXO@CeO2 effectively scavenged reactive oxygen species (ROS), reduced ROS-mediated apoptosis, stabilized mitochondrial membrane potential, and modulated inflammation by downregulating pro-inflammatory cytokines (IL-1β, IL-6) and upregulating anti-inflammatory IL-10. It also exhibited pro-angiogenic effects while preserving neuronal structure and function. In a murine photothrombotic stroke model, the hydrogel alleviated cerebral oxidative stress in the acute phase and promoted microglial polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. During recovery, it improved local cerebral blood flow and led to sustained improvements in neurobehavioral function. In summary, this injectable hydrogel enables sustained codelivery of exosomes and cerium oxide, offering a combined therapy integrating antioxidant and exosome-mediated reparative effects for ischemic stroke. Collectively, this dual strategy simultaneously mitigates acute oxidative damage and promotes long-term neurovascular repair.
Yuling Zhao, Wen Zhang, Yue Wang et al.· ACS Applied Materials and In...· 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
Intervertebral disc degeneration (IVDD), primarily driven by oxidative stress and inflammation, significantly impacts patient quality of life. Current therapies lack efficacy, highlighting the need for novel treatment strategies. This study investigates the protective effect of antioxidant hydrogel microspheres containing black phosphorus (BP) nanosheets and extracellular vesicles (EVs), fabricated using a microfluidic technology-based delivery system, designated as EVs@BPMS. In vitro analyses of EVs@BPMS revealed that BP nanosheets enhanced the antioxidant capacity of the hydrogel microspheres. The EVs@BPMS system functioned through the sustained release of extracellular vesicles. These vesicles collectively mitigated oxidative damage by scavenging reactive oxygen species (ROS), reducing oxidative stress, suppressing cellular senescence, and ultimately restoring extracellular matrix homeostasis in nucleus pulposus cells. Transcriptomic analysis further elucidated that the microspheres inhibited inflammatory responses via the IL-17-ferroptosis pathway, providing a theoretical basis for the development of targeted therapeutic interventions. In vivo studies confirmed the protective efficacy of EVs@BPMS in a rat model of IVDD, demonstrating substantial attenuation of disc degeneration. The findings underscored the innovative capacity of antioxidant hydrogel microspheres in regulating oxidative stress and maintaining cellular homeostasis. Moreover, they highlighted the potential of these microspheres for clinical application in degenerative disc disease.
C. A, Haozhe Cheng, Guangzi Chen et al.· Journal of Nanobiotechnology· 0 citations