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The prevalence of central nervous system (CNS) diseases is on the rise as the population ages. The presence of various obstacles, particularly the blood-brain barrier (BBB), poses a challenge for drug delivery to the CNS. An expanding body of study suggests that gut microbiota (GM) plays an important role in CNS diseases. The communication between GM and CNS diseases has received increasing attention. Accumulating evidence indicates that the GM can modulate host signaling pathways to regulate distant organ functions by delivering bioactive substances to host cells via bacterial extracellular vesicles (BEVs). BEVs have emerged as a promising platform for the treatment of CNS diseases due to their nanostructure, ability to penetrate the BBB, as well as their low toxicity, high biocompatibility, ease of modification and large-scale culture. Here, we discuss the biogenesis, internalization mechanism and engineering modification methods of BEVs. We then focus on the use and potential role of BEVs in the treatment of CNS diseases. Finally, we outline the main challenges and future prospects for the application of BEVs in CNS diseases. We hope that the comprehensive understanding of the BEVs-based gut-brain axis will provide new insights into the treatment of CNS diseases. [Display omitted] • Bacterial extracellular vesicles (BEVs) offer a novel mode of Gut-Brain axis. • The role of BEVs in the treatment of central nervous system (CNS) diseases. • Engineered BEVs show great therapeutic potential for CNS diseases. • The engineering strategies of modifying BEVs for CNS diseases were summarized. [ABSTRACT FROM AUTHOR]

The regeneration of weight-bearing bone defects and critical-sized cartilage defects remains a significant challenge. A wide range of nano-biomaterials are available for the treatment of bone/cartilage defects. However, their poor compatibility and biodegradability pose challenges to the practical applications of these nano-based biomaterials. Natural biomaterials inspired by the cell units (e.g., nucleic acids and proteins), have gained increasing attention in recent decades due to their versatile functionality, compatibility, biodegradability, and great potential for modification, combination, and hybridization. In the field of bone/cartilage regeneration, natural nano-based biomaterials have presented an unparalleled role in providing optimal cues and microenvironments for cell growth and differentiation. In this review, we systematically summarize the versatile building blocks inspired by the cell unit used as natural nano-based biomaterials in bone/cartilage regeneration, including nucleic acids, proteins, carbohydrates, lipids, and membranes. In addition, the opportunities and challenges of natural nano-based biomaterials for the future use of bone/cartilage regeneration are discussed. [ABSTRACT FROM AUTHOR]

To sum up, Bcl-3 was decreased during BMSCs senescence, and the supply of Bcl-3 could protect BMSCs from aging. Skeletal aging is characterized by progressive bone loss and increased marrow adiposity.1,2 Age-related bone loss impairs the exercise activity of patients and increases the risk of fracture. (F) Bcl-3, Ac-K49- -catenin and -catenin were analysed by immunoblot in control and Bcl-3-knockdown BMSCs after treated with Wnt 3a for 0 h or 4 h. (G) The levels of Bcl-3 in nuclear and cytoplasmic. B-cell lymphoma-3 controls mesenchymal stem cell commitment and senescence during skeletal aging. [Extracted from the article]

• Hamburger-Like Structural Innovation: Redefined periosteal design with a novel hamburger-like structure, significantly enhancing mechanical stability and transferability. • Macrophage Integration for Accelerated Osteogenesis: The integration of M2-polarized macrophages into BMSC layers, which significantly speed up bone formation and setting a new precedent in the field. • Oxygenation System for Enhanced Viability and Neovascularization: An advanced oxygen-controlled release system (up to 30 days) to combat hypoxic apoptosis in high-density cell layers, creating an optimal microenvironment for neovascularization and bone regeneration. The periosteum is pivotal in bone repair, serving as a key facilitator for new bone formation through its osteoimmunomodulation and neovascularization. However, autologous periosteum sources are limited, and traditional periosteal tissue engineering makes it difficult to mimic these functions of periosteum through simple structural design. In this study, we present a biomimetic nutrient periosteum with a hamburger-like structure. The middle layer is a mixed cell sheet composed of million level of bone marrow stromal cells (BMSCs) and M2 macrophages. Silk protein based-hydrogel layer encapsulating porous PLLA microspheres and CaO 2 nanoparticles was placed on the top and bottom layers of the cell sheets. The heterogeneous hydrogel enabled not only mechanical stability of the cell sheets, but also slow-releasement of oxygen from CaO 2 up to 30 days, which further enhances the viability of the cell sheets. That is, it closely mimics the structure and functionality of natural periosteum, effectively replicating its regenerative microenvironment. This hamburger-like biomimetic nutrient periosteum not only facilitates the transition of macrophages to a pro-healing M2 phenotype but also enhances the osteogenic differentiation of BMSCs and angiogenesis of human umbilical vein endothelial cells (HUVECs). Importantly, these effects have been validated in vivo in a critical-size bone defect model, underlining the potential of this biomimetic nutrient periosteum as an effective approach for advanced bone repair. [ABSTRACT FROM AUTHOR]

Osteoporosis (OP), characterized by decreased bone density and destruction of bone microstructure, is a common systemic bone disease in the elderly. Conventional therapies suffer from poor targeting and long-term toxicity. Engineered bacterial extracellular vesicles (BEVs) containing bioactive molecules show great potential as alternative OP therapies. Here, we developed a delivery system based on BEVs secreted probiotic Lactobacillus rhamnosus GG (LGG). Bone-targeting peptides were anchored on the LGG-EVs membranes, which endowed LGG-EVs the ability to deliver intrinsic miRNA to bone microenvironment. Bone-targeted LGG-EVs (BT-LGG-EVs) exhibited great bone targeting capability without significant toxicity. BT-LGG-EVs not only promoted osteogenic differentiation and mineralization but also inhibited the formation of osteoclasts. Furthermore, BT-LGG-EVs were demonstrated to be able to attenuate the OVX-induced osteoporotic phenotypes. Our study demonstrated that BT-LGG-EVs hold great promise for use as an innovative, safe, and effective solution for the treatment of OP. [ABSTRACT FROM AUTHOR]

Teriparatide, also known as 1-34 parathyroid hormone (PTH (1-34)), is commonly used for the treatment of osteoporosis in postmenopausal women. But its therapeutic application is restricted by poor metabolic stability, low bioavailability, and rapid clearance. Herein, PTHG2, a glycosylated teriparatide derivative, is designed and synthesized to improve PTH stability and exert more potent antiosteoporosis effect. Surface plasmon resonance (SPR) analysis shows that PTHG2 combines to PTH 1 receptor. Additional acetylglucosamine covalent bonding in the first serine at the N terminal of PTH (1-34) improves stability and increases protein hydrolysis resistance. Intermittent administration of PTHG2 preserves bone quality in ovariectomy- (OVX-) induced osteoporosis mice model, along with increased osteoblastic differentiation and bone formation, and reduced marrow adipogenesis. In vitro, PTHG2 inhibits adipogenic differentiation and promotes osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs). For molecular mechanism, PTHG2 directs BMSCs fate through stimulating the cAMP-PKA signaling pathway. Blocking PKA abrogates the pro-osteogenic effect of PTHG2. In conclusion, our study reveals that PTHG2 can accelerate osteogenic differentiation of BMSCs and inhibit adipogenic differentiation of BMSCs and show a better protective effect than PTH (1-34) in the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

Teriparatide, also known as 1-34 parathyroid hormone (PTH (1-34)), is commonly used for the treatment of osteoporosis in postmenopausal women. But its therapeutic application is restricted by poor metabolic stability, low bioavailability, and rapid clearance. Herein, PTHG2, a glycosylated teriparatide derivative, is designed and synthesized to improve PTH stability and exert more potent antiosteoporosis effect. Surface plasmon resonance (SPR) analysis shows that PTHG2 combines to PTH 1 receptor. Additional acetylglucosamine covalent bonding in the first serine at the N terminal of PTH (1-34) improves stability and increases protein hydrolysis resistance. Intermittent administration of PTHG2 preserves bone quality in ovariectomy- (OVX-) induced osteoporosis mice model, along with increased osteoblastic differentiation and bone formation, and reduced marrow adipogenesis. In vitro, PTHG2 inhibits adipogenic differentiation and promotes osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs). For molecular mechanism, PTHG2 directs BMSCs fate through stimulating the cAMP-PKA signaling pathway. Blocking PKA abrogates the pro-osteogenic effect of PTHG2. In conclusion, our study reveals that PTHG2 can accelerate osteogenic differentiation of BMSCs and inhibit adipogenic differentiation of BMSCs and show a better protective effect than PTH (1-34) in the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]