Jul 2026· Advancement of science· 0 citations· 50 references
Medicine
TL;DR
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.
Abstract
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.
Osteoarthritis (OA) progression is driven by inflammatory mediators and immune dysregulation within the joint. Curcumin (Cur) possesses multi‐target therapeutic potential. However, its clinical application is limited by poor solubility and a short half‐life. In this study, we developed injectable Cur‐loaded GelMA microspheres (Cur‐MS) and evaluated their effects in IL‐1β stimulated chondrocytes, cartilage organoids, and a monosodium iodoacetate (MIA) induced rat OA model, complemented by public transcriptomic analysis (GSE114007). The Cur‐MS demonstrated uniform size distribution, favorable biocompatibility, and sustained curcumin release. Treatment with Cur‐MS significantly reduced chondrocyte apoptosis, reactive oxygen species levels, and hypertrophic markers; restored COL‐II and ACAN synthesis; and downregulated MMP13 and inflammatory gene expression. In vivo, Cur‐MS improved joint space, alleviated pain, decreased synovial CD68 positive macrophage infiltration and levels of IL‐6 and TNF‐α, and enhanced chondrogenic gene expression. Public transcriptomic data corroborated these findings, revealing upregulation of MMP13 and downregulation of SOX9 in OA cartilage, consistent with our experimental targets. Collectively, this study provides the first multi‐model evidence combined with transcriptomic validation, demonstrating that Cur‐MS not only directly protects chondrocytes and restores extracellular matrix homeostasis but also modulates the joint inflammatory immune microenvironment. These findings suggest that Cur‐MS represents a promising locally sustained‐release therapeutic strategy for OA.
Bin Jiang, Xin Jiang, Shaobo Li et al.· Chemical Biology and Drug De...· 0 citations
Calvarial defect repair is frequently limited by immune dysregulation and insufficient coupling with bone regeneration. This study investigated the regulatory role of reticulocalbin‐2 (RCN2) in macrophages and evaluated a biomimetic periosteum‐bone bilayer scaffold (PB‐BLS) designed to deliver RCN2‐modified M2 macrophage‐derived exosomes (RCN2‐Exos). A photocrosslinkable periosteum‐like hydrogel was prepared from decellularized periosteal matrix (DPM), methacrylic anhydride‐modified DPM, and gelatin methacryloyl (GelMA), and was loaded with RCN2‐Exos. A zinc‐substituted tricalcium phosphate (Zn‐TCP)/chitosan (CS) bone‐like scaffold was fabricated by three‐dimensional printing and integrated with the periosteum‐like layer to form PB‐BLS. Material characterization confirmed favorable mechanical properties and controllable exosome release. In vivo studies using calvarial defect models and RCN2‐knockout controls showed that RCN2 deficiency impaired bone repair and aggravated inflammatory responses. PB‐BLS promoted M2 macrophage polarization, enhanced skeletal stem cell (SSC) migration and osteogenic differentiation in vitro, and significantly increased bone volume fraction (BV/TV) and bone mineral density (BMD) in vivo. Single‐cell RNA sequencing and cell‐cell communication analyses indicated that PB‐BLS remodeled the local immuno‐osteogenic microenvironment and enhanced key signaling axes, including SPP1‐CD44 and CXCL12‐CXCR4. These findings identify RCN2 as a pivotal mediator linking macrophage immune phenotype with osteogenic fate and support RCN2‐Exos‐loaded PB‐BLS as a promising strategy for bone defect repair.
Jiajia Lu, Sheng Zhou, Long Yang et al.· Advanced Functional Material...· 1 citation
The repair of osteoporotic bone defects presents a formidable challenge due to the disrupted osteogenic‐adipogenic equilibrium within the bone marrow microenvironment. To address the limitations of monotherapies in regulating this pathological condition, this study engineers an enzyme‐responsive delivery platform, the puerarin‐reinforced nucleic acid‐based nanoassembly (Pue@NB), via structural reprogramming of tetrahedral framework nucleic acid (tFNA). This system enables precise co‐encapsulation and intracellular co‐delivery of osteogenic microRNA (miR‐335‐5p) and puerarin (Pue). While preserving the biocompatibility and cellular entry efficiency of tFNA, Pue@NB incorporates an embedded DNA‐RNA hybrid bio‐switch that responds to endogenous RNase H, enabling structural transformation and coordinated release of both therapeutic agents. In vitro, beyond promoting the migration of bone marrow mesenchymal stem cells (BMSCs), Pue@NB also exhibits a bidirectional regulatory capacity for BMSCs differentiation: its pro‐osteogenic and anti‐adipogenic effects are accompanied by increased hedgehog‐related signaling markers, upregulated TGF‐β1, and suppressed PPARγ/FABP4 expression. In an ovariectomy‐induced osteoporotic bone defect model, Pue@NB substantially accelerated bone regeneration, restored bone mineral density, and improved trabecular microstructure. This work elucidates a synergistic therapeutic strategy that integrates genetic and small‐molecule drugs via nucleic acid nanostructure reengineering, providing foundations for developing next‐generation dynamic nanomaterials for recalcitrant tissue defects.
Yuxuan Zhao, Kaiwen Zhang, Xin-Man Mo et al.· Advanced Functional Material...· 0 citations
Osteoarthritis (OA) is driven by intertwined pathological processes, including chronic inflammation, oxidative stress, immune imbalance, hypoxia, and aberrant angiogenesis, while current noninvasive therapies remain limited by insufficient deep‐joint delivery and poor multidimensional regulation. Here, an extracellular vesicle (EV)‐centered, near‐infrared (NIR)‐responsive transdermal platform is developed to address these challenges. Apple‐derived extracellular vesicles (AEVs) are used as intrinsically bioactive nanocarriers to co‐deliver berberine (BBR) and piperine (PIP), and are integrated into a biocompatible dextran/alginate hydrogel containing graphene oxide (GO). Under NIR stimulation, GO provides on‐demand energy conversion that supports mild hyperthermia‐assisted barrier loosening together with potential photo‐redox‐associated microenvironment modulation, thereby enhancing local therapeutic availability while maintaining a safe thermal window. In vivo assessment of TRPV1 expression and tight‐junction‐related responses provides supportive indication for transport‐associated modulation, whereas ex vivo diffusion findings are interpreted as barrier‐level permeation evidence rather than direct confirmation of in vivo mechanisms. In an OA rat model, the NIR‐activated platform is associated with reduced joint inflammation and edema, attenuated oxidative stress, improved macrophage polarization toward an anti‐inflammatory phenotype, enhanced gait‐related joint function, and preservation of cartilage structure. This study establishes a noninvasive, stimulus‐responsive transdermal strategy for localized and multifaceted OA microenvironment modulation.
Yu-Wen Tseng, Pei-Wei Weng, Hsien-Tsung Lu et al.· Advanced Healthcare Material...· 0 citations
Osteoarthritis (OA) arises from chondrocyte senescence driven by intertwined oxidative stress and abnormal m6A methylation, with few treatments targeting both pathological pathways. Lycopene, an antioxidant, is limited by poor bioavailability, whereas Wilms tumor 1-associating protein (WTAP), a core m6A methyltransferase, has no specific inhibitors. Herein, we fabricated cartilage-targeted HPcLW nanoparticles (∼250 nm) via electrostatic self-assembly of human serum albumin (HSA) and poly-L-lysine (PLL) with collagen II-binding peptide, co-loaded with lycopene and WTAP siRNA. The targeting modification extended joint fluorescence retention to 10 days after intra-articular injection with good serum stability and biosafety. In aged mice and medial meniscus (DMM)-induced OA mouse models, intra-articular HPcLW attenuated cartilage degeneration, restored COL2 expression, and suppressed MMP13 levels. Mechanistically, WTAP siRNA suppressed m6A modification to downregulate PAI-1 expression, while lycopene scavenged ROS and protected siRNA integrity, cooperatively disrupting the WTAP/PAI-1 axis and alleviating mitochondrial dysfunction. By integrating antioxidant and epigenetic strategies, HPcLW counteracts the senescence loop, establishing the WTAP/PAI-1 axis as a therapeutic target and highlighting co-delivery nanomedicine for age-related joint diseases.
Xueying An, Hantao Cai, Wen-Shu Wu et al.· Bioactive Materials· 0 citations