Jul 2026· Advances in Materials· pp.
e74189
· 0 citations· 21 references
Medicine
TL;DR
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.
Abstract
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.
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.
Zhiwei Liao, Guoqiang Yin, Jing-Pei Liu et al.· Journal of Controlled Releas...· 0 citations
Healing of diabetic wounds is severely hindered by a persistent vicious cycle of bacterial infection and metabolic disorders. Pathological microenvironments, characterized by high glucose levels and excessive reactive oxygen species (ROS), exacerbate chronic inflammation and impede the transition of macrophages toward a pro-healing phenotype. To address these challenges, we developed a multi-stimuli-responsive composite hydrogel platform (GHFA/Cu@TA) by integrating fulvic acid (FA) and copper-tannic acid nanozymes (Cu@TA NPs) into a dynamic covalent network composed of methacrylated gelatin (GelMA) and phenylboronic acid-modified hyaluronic acid (HA-PBA). This platform implements a self-feedback mechanism to restore metabolic homeostasis: glucose-triggered release of Cu@TA NPs effectively scavenges microenvironmental ROS to drive tissue microenvironment remodeling, thereby decelerating responsive hydrogel degradation upon homeostasis normalization to ensure synchronized on-demand drug delivery. Intelligently released FA promotes M2 macrophage polarization to reshape the immune microenvironment, while Cu@TA NPs achieve photothermal biofilm eradication under near-infrared (NIR) light. This "metabolic sensing-feedback regulation-homeostasis reconstruction" strategy offers a distinct therapeutic framework for addressing diabetic wound and contributes to the rational design of bioactive dressings with stimuli responsiveness.
Na Yang, Lingling Tang, Huanghe Zeng et al.· International Journal of Bio...· 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
In vivo studies in diabetic Sprague-Dawley rats model demonstrated that CC-pMnO2-Vet@PNAA established a coordinated immune-mechanical microenvironment, achieving rapid and scar-free wound healing.
The structural deterioration observed in maxillofacial skeletal conditions and associated mucosal tissues is fundamentally governed by a vicious cycle of sustained immunological activation and severe oxidative stress. Consequently, this continuous reactive oxygen species (ROS) accumulation directly fuels the etiology of debilitating diseases, notably bisphosphonate-related osteonecrosis of the jaw (BRONJ), oral submucous fibrosis (OSF), and periodontitis. Conventional therapeutic regimens often exhibit compromised localized efficacy or induce severe systemic adverse effects. To surmount these delivery impediments, tetrahedral framework nucleic acids (tFNAs) have emerged as versatile three-dimensional DNA nanostructure platforms. Characterized by high structural rigidity, intrinsic radical-scavenging bioactivity, rapid cellular internalization, and precise programmability, tFNAs enable the targeted co-delivery of regulatory oligonucleotides, small-molecule antioxidants, and bioactive peptides. This review evaluates how ROS modulate downstream oxidative stress and inflammatory networks to drive tissue destruction and bone metabolic imbalances. Furthermore, we examine structural optimization strategies, including the integration of tFNAs into hydrogel matrices, the incorporation of pH-responsive lysosomal escape elements, and the conjugation of targeting surface ligands. Preclinical evidence demonstrates that functionalized tFNAs networks effectively disrupt the self-amplifying oxidative stress-inflammation cascade, remodeling hostile microenvironments to promote structural tissue regeneration. To conclude, this review delineates major clinical translation hurdles, including industrial scale-up and pharmacokinetic elimination profiles. These considerations establish a conceptual baseline for engineering future targeted oxidative therapies.
Jiahui Xiong, Wuxiao Cui, Xiao Fu et al.· Oral Science and Homeostatic...· 0 citations
