The high prevalence and significant impact of osteoporosis make it a leading cause of disability and mortality among older individuals. Neural networks have been reported to have a crucial role in both the physiological and pathological progression of osteoporosis, suggesting neural modulation could be used as an underlying strategy to attenuate the progression of osteoporosis. In this study, we firstly identified the significant relationship between vagus nerve and bone remodeling through artificial intelligence (AI)-based knowledge mining. Subsequently, iron oxide nanoparticles were incorporated into injectable hydrogels (termed M-Gels), which were then directly injected to envelop a single vagus nerve in the left neck of rats to prolong the retention issue in peripheral tissues (up to 20 weeks). Magnetic vagus nerve stimulation (mVNS) showed a rapid response characteristic of vagus activation. Notably, the mVNS administered at 20 Hz twice daily for 15 min over 16 weeks effectively improved bone metabolism in vivo. Using AI, we discovered that gut microbiota is an underlying cause of this phenomenon. This innovative mVNS method demonstrated the correlation between the vagus nerve and bone remodeling, revealing promising potential for osteoporosis therapy by long term mVNS.

Tendinopathy is a common and complex musculoskeletal disorder, unfortunately current clinical strategies for tendinopathy have low therapeutic efficacy because of complicated pathogenesis. Oxidative stress is considered as the major cause of tendinopathy as well as the important target, but still lacking ideal antioxidant solution. To this end, an efficient reactive oxygen species (ROS) biocatalyst, PtIrRuRhCu high-entropy alloy nanozyme (HEANZ), has been designed for treatment of tendinopathy. The non-ionic block copolymer (polyvinyl pyrrolidone) coated PtIrRuRhCu HEANZ with size of ~ 4.0 nm exhibits good biocompatibility and multiple enzyme-like antioxidant activity (including peroxidase, catalase and superoxide dismutase (SOD)-like) to modulate ROS. The therapeutic efficacy of PtIrRuRhCu HEANZ in tendinopathy has been systematically demonstrated in vitro and in vivo. PtIrRuRhCu HEANZ can alleviate the t-Butyl hydroperoxide (TBHP) stimulated tendinopathy by clearing ROS, reducing inflammation and restoring mitochondrial autophagy. Using phosphoglycerate mutase family member 5 (PGAM5) siRNA and FUN14 domain containing protein 1 (FUNDC1) siRNA for intervention, we clearly revealed that PtIrRuRhCu HEANZ promots mitochondrial autophagy through upregulating the PGAM5/FUNDC1/glutathione peroxidase 4 (GPX4) axis. This study provides a nanozyme strategy for the antioxidant treatment of tendinopathy and provides insights into the therapeutic mechanism.

Bone tissue engineering provides a promising strategy for the treatment of bone defects. Nonetheless, the clinical utilization of biomaterial-based scaffolds is constrained by their inadequate mechanical strength and absence of osteo-inductive properties. Here, we proposed to endow nano-scaffold (NS) constructed by coaxial electrospinning technique with enhanced osteogenic bioactivities and mechanical properties by incorporating biocompatible magnetic iron oxide nanoparticles (IONPs) and icaritin (ICA). Four types of nano-scaffolds (NS, ICA@NS, NS-IONPs and ICA@NS-IONPs) were prepared. The incorporation of ICA and IONPs minimally impact their surface morphological and chemical properties. IONPs enhanced the mechanical properties of NS scaffolds, including hardness, tensile strength, and elastic modulus. In vitro assessments demonstrated that ICA@NS-IONPs exhibited enhanced osteogenic bioactivities towards mouse calvarial pre-osteoblast cell line MC3T3-E1 as evidenced by detecting the alkaline phosphatase (ALP) activity level, expressions of osteogenesis-related genes and proteins as well as mineralized nodule formation. Mechanistic investigations revealed that MEK/ERK (MAP kinase-ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK)) signaling pathway could offer a plausible explanation for the osteogenic differentiation of MC3T3-E1 cells induced by ICA@NS-IONPs. Furthermore, the implantation of nano-scaffolds in rat skull defects exhibited a substantial improvement in in vivo bone regeneration. Therefore, IONPs and ICA incorporated coaxial electrospinning nano-scaffolds present a novel strategy for the optimization of scaffolds for bone tissue engineering.

Osteoporosis is a metabolic dysregulation of bone that occurs mainly in postmenopausal women, and the hyperfunction of osteoclasts is the primary contributor to postmenopausal osteoporosis. However, the development of effective therapeutic drugs and precise delivery systems remains a challenge in the field of anti-absorption therapy. Here, we reported the α-cyperone (α-CYP) for anti-osteoporosis and developed a liposome-based nano-drug delivery system of α-CYP, that specifically targets the bone resorption interface. Firstly, we found that the α-CYP, one of the major sesquiterpenes of Cyperus rotundus L., attenuated the progression of osteoporosis in ovariectomized (OVX) mice and down-regulated the expression of phosphorylated proteins of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt), causing down-regulation of osteoclast-related genes/proteins and curbing osteoclast differentiation. Furthermore, α-CYP reversed the activation of osteoclastic differentiation and enhanced osteoporosis-related proteins expression caused by PI3K/Akt agonist (YS-49). More importantly, we adopted the osteoclastic resorption surface targeting peptide Asp8 and constructed the liposome (lipαC@Asp8) to deliver α-CYP to osteoclasts and confirmed its anti-osteoporosis effect and enhanced osteoclast inhibition by blocking PI3K/Akt axis. In conclusion, this study demonstrated that α-CYP inhibits osteoclast differentiation and osteoporosis development by silencing PI3K/Akt pathway, and the liposome targeting delivery systems loaded with α-CYP might provide a novel and effective strategy to treat osteoporosis.

Tissue engineering scaffolds have presented effective value in bone repair. However, the integration of the diverse components, complex structures, and multifunction to impart the scaffolds with improved applicability is still a challenge. Here, we propose a novel fish-derived scaffold combined with photothermal therapy and mesenchymal stem cells (MSCs) to promote bone regeneration. The fish-derived scaffold is composed of the decellularized fish scale and gelatin methacrylate synthesized from fish gelatin (fGelMA), which can promote the proliferation and osteogenesis of MSCs with no obvious immunological rejection. Furthermore, the black phosphorus (BP) nanosheets are incorporated into the fGelMA hydrogel network, which can endow the hydrogel with the capacity of photothermal conversion stimulated by near-infrared (NIR) light. The fish-derived scaffold can promote the osteogenesis process of MSCs with higher expression of osteogenic markers and higher mineralization assisted by the NIR light in vitro. The regeneration of mice calvarial defect has also been accelerated by the scaffold with photothermal therapy and MSCs. These results suggest that the fish-derived scaffold, photothermal therapy, and MSCs-based regenerative therapy is a promising clinical strategy in bone regeneration.