Hsa_circ_0004872 mitigates proliferation, metastasis and immune escape of meningioma cells by suppressing PD-L1.

Meningioma is a prevalent intracranial malignancy known for its aggressive growth. Circular RNAs (circRNAs) play a crucial role in the development of various cancers. However, their involvement in meningioma remains understudied. This study aimed to investigate the function and underlying mechanism of hsa_circ_0004872 in meningioma. The molecular expression of hsa_circ_0004872, PD-L1 and EIF4A3 was identified by RT-qPCR and/or western blot assays. Cell viability, migration, and invasion were assessed through CCK-8 and Transwell assays, respectively. Cytotoxicity was determined using an LDH assay, and cell apoptosis was monitored by flow cytometry. The RNA and protein interactions were assessed through RNA-protein immunoprecipitation (RIP) and RNA pull down analyses. Our findings revealed that hsa_circ_0004872 expression was significantly downregulated in both meningioma tissue samples and cells. Overexpression of hsa_circ_0004872 inhibited the proliferation, metastasis, and immune escape of meningioma cells, as well as enhanced the cytotoxicity of CD8+ T cells by suppressing PD-L1. Furthermore, hsa_circ_0004872 directly interacted with EIF4A3, leading to the degradation of PD-L1 mRNA. Finally, inhibiting EIF4A3 improved the proliferation, metastasis, and immune escape of meningioma cells, as well as the cytotoxicity of CD8+ T cells. Our study demonstrated that hsa_circ_0004872 mitigated the proliferation, metastasis,and immune escape of meningioma cells by targeting the EIF4A3/PD-L1 axis. These findings suggested that hsa_circ_0004872 and EIF4A3 might serve as promising biological markers and therapeutic targets for meningioma treatment.

Regulating the bioactivity of non-glycosylated recombinant human bone morphogenetic protein-2 to enhance bone regeneration.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is the predominant growth factor that effectively induces osteogenic differentiation in orthopedic procedures. However, the bioactivity and stability of rhBMP-2 are intrinsically associated with its sequence, structure, and storage conditions. In this study, we successfully determined the amino acid sequence and protein secondary structure model of non-glycosylated rhBMP-2 expressed by an E. coli expression system through X-ray crystal structure analysis. Furthermore, we observed that acidic storage conditions enhanced the proliferative and osteoinductive activity of rhBMP-2. Although the osteogenic activity of non-glycosylated rhBMP-2 is relatively weaker compared to glycosylated rhBMP-2; however, this discrepancy can be mitigated by incorporating exogenous chaperone molecules. Overall, such information is crucial for rationalizing the design of stabilization methods and enhancing the bioactivity of rhBMP-2, which may also be applicable to other growth factors.

Boron Cluster Renders Organic Radicals Water-Stable for Photothermal Anti-Infections.

Water-stable organic radicals are promising photothermal conversion candidates for photothermal therapy (PTT). However, organic radicals are usually unstable in biological environments, which greatly hinders their wide application. Here, we have developed a chaotropic effect-based and photoinduced water-stable supramolecular radical (MB12-2) for efficient antibacterial PTT. The supramolecular radical precursor MB12-1 was constructed by the chaotropic effect between closo-dodecaborate cluster (B12H122-) and N,N'-dimethylated dipyridinium thiazolo [5,4-d] thiazole (MPT2+). Subsequently, with triethanolamine (TEOA) serving as an electron donor, MB12-1 could transform to its radical form MB12-2 through photoinduced electron transfer (PET) under 435-nm laser irradiation. The N2 adsorption-desorption analysis confirmed that MB12-2 was tightly packed through the introduction of B12H122-, which effectively enhanced its stability via a spatial site-blocked effect. Moreover, the half-life of MB12-2 in water was calculated through ultraviolet-visible light (UV-vis) absorption spectra results for periods as long as 20 days. In addition, in the skin infection model, MB12-2, as a wound dressing, showed remarkable photothermal antibacterial activity (>97%) under 660-nm laser irradiation and promoted wound healing. This study presents a simple method for designing long-term water-stable supramolecular radicals, offering a novel avenue for noncontact treatments for bacterial infections.

Biomaterial design for regenerating aged bone: materiobiological advances and paradigmatic shifts.

China's aging demographic poses a challenge for treating prevalent bone diseases impacting life quality. As bone regeneration capacity diminishes with age due to cellular dysfunction and inflammation, advanced biomaterials-based approaches offer hope for aged bone regeneration. This review synthesizes materiobiology principles, focusing on biomaterials that target specific biological functions to restore tissue integrity. It covers strategies for stem cell manipulation, regulation of the inflammatory microenvironment, blood vessel regeneration, intervention in bone anabolism and catabolism, and nerve regulation. The review also explores molecular and cellular mechanisms underlying aged bone regeneration and proposes a database-driven design process for future biomaterial development. These insights may also guide therapies for other age-related conditions, contributing to the pursuit of 'healthy aging'.

Swift Covalent Gelation Coupled with Robust Wet Adhesive Powder: A Novel Approach for Acute Massive Hemorrhage Control in Dynamic and High-Pressure Wound Environments.

The quest for efficient hemostatic agents in emergency medicine is critical, particularly for managing massive hemorrhages in dynamic and high-pressure wound environments. Traditional self-gelling powders, while beneficial due to their ease of application and rapid action, fall short in such challenging conditions. To bridge this gap, the research introduces a novel self-gelling powder that combines ultrafast covalent gelation and robust wet adhesion, presenting a significant advancement in acute hemorrhage control. This ternary system comprises ε-polylysine (ε-PLL) and 4-arm polyethylene glycol succinyl succinate (4-arm-PEG-NHS) forming the hydrogel framework. Na2HPO4 functions as the "H+ sucker" to expedite the amidation reaction, slashing gelation time to under 10 s, crucial for immediate blood loss restriction. Moreover, PEG chains' hydrophilicity facilitates efficient absorption of interfacial blood, increasing the generated hydrogel's cross-linking density and strengthens its tissue bonding, thereby resulting in excellent mechanical and wet adhesion properties. In vitro experiments reveal the optimized formulation's exceptional tissue compliance, procoagulant activity, biocompatibility and antibacterial efficacy. In porcine models of heart injuries and arterial punctures, it outperforms commercial hemostatic agent Celox, confirming its rapid and effective hemostasis. Conclusively, this study presents a transformative approach to hemostasis, offering a reliable and potent solution for the emergency management of massive hemorrhage.

Decellularized extracellular matrix enriched with GDNF enhances neurogenesis and remyelination for improved motor recovery after spinal cord injury.

Motor functional improvement represents a paramount treatment objective in the post-spinal cord injury (SCI) recovery process. However, neuronal cell death and axonal degeneration following SCI disrupt neural signaling, impeding the motor functional recovery. In this study, we developed a multifunctional decellularized spinal cord-derived extracellular matrix (dSECM), crosslinked with glial cell-derived neurotrophic factor (GDNF), to promote differentiation of stem cells into neural-like cells and facilitate axonogenesis and remyelination. After decellularization, the immunogenic cellular components were effectively removed in dSECM, while the crucial protein components were retained which supports stem cells proliferation and differentiation. Furthermore, sustained release of GDNF from the dSECM facilitated axonogenesis and remyelination by activating the PI3K/Akt and MEK/Erk pathways. Our findings demonstrate that the dSECM-GDNF platform promotes neurogenesis, axonogenesis, and remyelination to enhance neural signaling, thereby yielding promising therapeutic effects for motor functional improvement after SCI. STATEMENT OF SIGNIFICANCE: The dSECM promotes the proliferation and differentiation of MSCs or NSCs by retaining proteins associated with positive regulation of neurogenesis and neuronal differentiation, while eliminating proteins related to negative regulation of neurogenesis. After crosslinking, GDNF can be gradually released from the platform, thereby promoting neural differentiation, axonogenesis, and remyelination to enhance neural signaling through activation of the PI3K/Akt and MEK/Erk pathways. In vivo experiments demonstrated that dSECM-GDNF/MSC@GelMA hydrogel exhibited the ability to facilitate neuronal regeneration at 4 weeks post-surgery, while promoting axonogenesis and remyelination at 8 weeks post-surgery, ultimately leading to enhanced motor functional recovery. This study elucidates the ability of neural regeneration strategy to promote motor functional recovery and provides a promising approach for designing multifunctional tissue for SCI treatment.

Sulfated Polysaccharide-Based Nanocarrier Drives Microenvironment-Mediated Cerebral Neurovascular Remodeling for Ischemic Stroke Treatment.

Stroke is a leading cause of global mortality and severe disability. However, current strategies used for treating ischemic stroke lack specific targeting capabilities, exhibit poor immune escape ability, and have limited drug release control. Herein, we developed an ROS-responsive nanocarrier for targeted delivery of the neuroprotective agent rapamycin (RAPA) to mitigate ischemic brain damage. The nanocarrier consisted of a sulfated chitosan (SCS) polymer core modified with a ROS-responsive boronic ester enveloped by a red blood cell membrane shell incorporating a stroke homing peptide. When encountering high levels of intracellular ROS in ischemic brain tissues, the release of SCS combined with RAPA from nanoparticle disintegration facilitates effective microglia polarization and, in turn, maintains blood-brain barrier integrity, reduces cerebral infarction, and promotes cerebral neurovascular remodeling in a mouse stroke model involving transient middle cerebral artery occlusion (tMCAO). This work offers a promising strategy to treat ischemic stroke therapy.

The Effect of Process Parameters on the Temperature and Stress Fields in Directed Energy Deposition Inconel 690 Alloy.

Additive manufacturing (AM) technology has the advantages of designability, short process times, high flexibility, etc., making it especially suitable for manufacturing complex high-performance components for high-end industrial systems. However, the intensive temperature gradients caused by the rapid heating and cooling processes of AM can generate high levels of residual stresses, which directly affect the precision and serviceability of the components. Taking Inconel 690 alloy, which is widely used in nuclear power plants, as the research object, a thermo-coupled mechanical model of temperature field and residual stress field of directed energy deposition (DED) of Inconel 690 was established based on ABAQUS 2019 finite element software to study the influence of process parameters on the temperature history and the distribution of residual stresses in the DED process. The experimental results show that the peak temperature of each layer in the fabrication process increases with the increase in laser power and preheating temperature, and decreases with the increase in scanning speed and interlayer dwell time. Substrate preheating only has a large effect on the peak temperature of the first four layers. Residual stresses are mainly concentrated in the upper and middle parts, the bottom of the substrate, and the sides combined with the substrate, and the residual stresses increase with the increasing laser power and decrease with the increasing interlayer dwell time. Decreasing laser power, longer dwell time, higher preheating temperature, and appropriate scanning speed are beneficial for the reduction in residual stresses in Inconel 690 components. This research has important significance for the process design and residual stress modulation in the additive manufacturing of Inconel 690 alloy.

Comparison evaluation pretreatments on the quality characteristics, oxidative stability, and volatile flavor of walnut oil.

In this study, we applied various thermal pretreatment methods (e.g., hot-air, microwave, and stir-frying) to process walnut kernels, and conducted comparative analysis of the physicochemical properties, nutritional components, in vitro antioxidant activity, and flavor substances of the extracted walnut oil (WO). The results indicated that, thermal pretreatment significantly increased the extraction of total trace nutrients (e.g., total phenols, tocopherols, and phytosterols) in WO. The WO produced using microwave had 2316.71 mg/kg of total trace nutrients, closely followed by the stir-frying method, which yielded an 11.22% increase compared to the untreated method. The WO obtained by the microwave method had a higher Oxidative inductance period (4.05 h) and oil yield (2.48%). After analyzing the flavor in WO, we found that aldehydes accounted for 28.77% of the 73 of volatile compounds and 58.12% of the total flavor compound content in microwave-pretreated WO, these percentages were higher than those recorded by using other methods. Based on the comprehensive score obtained by the PCA, microwave-pretreatment might be a promising strategy to improve the quality of WO based on aromatic characteristics.

Biomaterial-assisted therapeutic cell production and modification in vivo.

Hematopoietic stem cell transplantation remains the preferred treatment for a variety of hematopoietic function disorders. To address the issue of limited numbers of hematopoietic stem/progenitor cells (HSPCs), significant progress has been made in the technology for ex vivo expansion of HSPCs. In addition, biomaterial-assisted in vivo production technology for therapeutic cells, including HSPCs, is gradually gaining attention. With the aid of specifically functional biomaterials, researchers can construct bone-like tissues exhibiting typical bone marrow-like structures (termed in vivo osteo-organoids in this article) for the production of therapeutic cells. These in vivo osteo-organoids mimic the native bone marrow niche and provide a microenvironment conducive to the expansion and differentiation of HSPCs. In this perspective article, we systematically summarize the history of in vivo osteo-organoids as a model for studying hematopoiesis and cancer metastasis and propose the challenges faced by the in vivo osteo-organoid production platform for therapeutic cells in terms of clinical translation. Ultimately, we hope to achieve functional customization of in vivo osteo-organoid-derived cells through continuously developed material design methods, so as to meet the treatment needs of different types of diseases and bring hope for life to more people.

In Vivo Osteo-organoid Approach for Harvesting Therapeutic Hematopoietic Stem/Progenitor Cells.

Hematopoietic stem cell transplantation (HSCT) requires a sufficient number of therapeutic hematopoietic stem/progenitor cells (HSPCs). To identify an adequate source of HSPCs, we developed an in vivo osteo-organoid by implanting scaffolds loaded with recombinant human bone morphogenetic protein-2 (rhBMP-2) into an internal muscle pouch near the femur in mice. After 12 weeks of implantation, we retrieved the in vivo osteo-organoids and conducted flow cytometry analysis on HPSCs, revealing a significant presence of HSPC subsets within the in vivo osteo-organoids. We then established a sublethal model of hematopoietic/immune system injury in mice through radiation and performed hematopoietic stem cell transplantation (HSCT) by injecting the extracted osteo-organoid-derived cells into the peripheral blood of radiated mice. The effect of hematopoietic recovery was evaluated through hematological, peripheral blood chimerism, and solid organ chimerism analyses. The results confirmed that in vivo osteo-organoid-derived cells can rapidly and efficiently reconstruct damaged peripheral and solid immune organs in irradiated mice. This approach holds potential as an alternative source of HSPCs for HSCT, offering benefits to a larger number of patients.

[Expert consensus on integrated traditional Chinese and western medicine diagnosis and treatment for osteoporotic fractures].

Osteoporotic fractures represent the most severe complications of osteoporosis,characterized by insidious onset,high mortality and disability rates,and a steadily increasing incidence,imposing a significant socioeconomic burden. Western medicine has advantages in diagnosis and surgical interventions,while traditional Chinese medicine excels in holistic management and the restoration of bodily equilibrium. The integration of both traditional Chinese medicine (TCM) and western medicine emerges as an effective therapeutic strategy for osteoporotic fractures. In order to propagate the concept of integrated diagnosis and treatment,foster the advancement of integrated medical techniques for osteoporotic fractures,and establish standardized and normative protocols for disease prevention,diagnosis,and treatment,a consensus expert group,led by Geriatric Branch of Chinese Geriatrics Society,the Young Osteoporosis Group of Orthopedics Branch of Chinese Medical Association,Osteoporosis Group of Orthopedics Branch of Chinese Physician Association,and Osteoporosis Professional Committee of the Shanghai Society of Integrated Traditional Chinese and Western Medicine,was established. This group engaged in deliberations and formulated the "Expert Consensus on Integrated Traditional Chinese and Western Medicine Diagnosis and Treatment of Osteoporotic Fractures" elucidating the concept of integrated medicine and offering recommendations in the domains of prevention,diagnosis,and treatment,with the aspiration of ameliorating the prognosis of osteoporotic fractures and enhancing the quality of life for these patients.

Bio-integrated scaffold facilitates large bone regeneration dominated by endochondral ossification.

Repair of large bone defects caused by severe trauma, non-union fractures, or tumor resection remains challenging because of limited regenerative ability. Typically, these defects heal through mixed routines, including intramembranous ossification (IMO) and endochondral ossification (ECO), with ECO considered more efficient. Current strategies to promote large bone healing via ECO are unstable and require high-dose growth factors or complex cell therapy that cause side effects and raise expense while providing only limited benefit. Herein, we report a bio-integrated scaffold capable of initiating an early hypoxia microenvironment with controllable release of low-dose recombinant bone morphogenetic protein-2 (rhBMP-2), aiming to induce ECO-dominated repair. Specifically, we apply a mesoporous structure to accelerate iron chelation, this promoting early chondrogenesis via deferoxamine (DFO)-induced hypoxia-inducible factor-1α (HIF-1α). Through the delicate segmentation of click-crosslinked PEGylated Poly (glycerol sebacate) (PEGS) layers, we achieve programmed release of low-dose rhBMP-2, which can facilitate cartilage-to-bone transformation while reducing side effect risks. We demonstrate this system can strengthen the ECO healing and convert mixed or mixed or IMO-guided routes to ECO-dominated approach in large-size models with clinical relevance. Collectively, these findings demonstrate a biomaterial-based strategy for driving ECO-dominated healing, paving a promising pave towards its clinical use in addressing large bone defects.

Materiobiomodulated ROS Therapy for De Novo Hair Growth.

Hair loss is characterized by the inability of hair follicles (HFs) to enter the telogen-anagen transition (TAT) and lack of de novo HFs. Current pharmaceutical therapies and surgical modalities have been largely limited to regulating hair regrowth efficiently without side effects and lacking treatment compliance. Here, this work proposes a materiobiomodulation therapy (MBMT), wherein polydopamine (PDA) nanoparticles with redox activity can be modulated to have a stoichiometric ROS (H2 O2 ) donating ability. These nanoparticles can intracellularly deliver ROS with high-efficiency via the clathrin-dependent endocytosis process. Utilizing homozygote transgenic HyPerion (a genetically-encoded H2 O2 biosensor) mice, this work also achieves in vivo dynamic monitoring of intracellular H2 O2 elevation induced by ROS donators. Subcutaneous administration with ROS donators results in rapid onset of TAT and subsequent hair regrowth with a specific ROS "hormesis effect." Mechanistically, ROS activate ß-catenin-dependent Wnt signaling, upregulating hair follicle stem cell expression. This work further develops a microneedles patch for transdermal ROS delivery, demonstrating long-term, low-dose ROS release. Unlike photobiomodulation therapy (PBMT), MBMT requires no external stimuli, providing a convenient and efficient approach for clinical hair loss treatment. This material-HF communication implicates new avenues in HF-related diseases, achieving targeted ROS delivery with minimal side effects.

Advancing homogeneous networking principles for the development of fatigue-resistant, low-swelling and sprayable hydrogels for sealing wet, dynamic and concealed wounds in vivo.

Effective sealing of wet, dynamic and concealed wounds remains a formidable challenge in clinical practice. Sprayable hydrogel sealants are promising due to their ability to cover a wide area rapidly, but they face limitations in dynamic and moist environments. To address this issue, we have employed the principle of a homogeneous network to design a sprayable hydrogel sealant with enhanced fatigue resistance and reduced swelling. This network is formed by combining the spherical structure of lysozyme (LZM) with the orthotetrahedral structure of 4-arm-polyethylene glycol (4-arm-PEG). We have achieved exceptional sprayability by controlling the pH of the precursor solution. The homogeneous network, constructed through uniform cross-linking of amino groups in protein and 4-arm-PEG-NHS, provides the hydrogel with outstanding fatigue resistance, low swelling and sustained adhesion. In vitro testing demonstrated that it could endure 2000 cycles of underwater shearing, while in vivo experiments showed adhesion maintenance exceeding 24 h. Furthermore, the hydrogel excelled in sealing leaks and promoting ulcer healing in models including porcine cardiac hemorrhage, lung air leakage and rat oral ulcers, surpassing commonly used clinical materials. Therefore, our research presents an advanced biomaterial strategy with the potential to advance the clinical management of wet, dynamic and concealed wounds.

Solvent-Triggered, Ultra-Adhesive, Conductive, and Biocompatible Transition Gels for Wearable Devices.

The development of robust adhesive, conductive, and flexible materials has garnered significant attention in the realm of human-machine interface and electronic devices. Conventional preparation methods to achieve these exceptional properties rely on incorporating highly polar raw materials, multiple components, or solvents. However, the overexposure of functional groups and the inherent toxicity of organic solvents often render gels non-stick or potentially biocompatible making them unsuitable for human-contact devices. In this study, a straightforward three-step strategy is devised for preparing responsive adhesive gels without complex components. Structurally conductive poly(N-(2-hydroxyethyl)-acrylamide-co-p-styrene sulfonate hydrate) (PHEAA-NaSS) gels are synthesized by integrating ionic and hydrophilic networks with distinct solvent effects. Initially, the in-suit formed PHEAA-NaSS networks are activated by dimethyl sulfoxide, which substantially increases intramolecular hydrogen bonding and enhances the matrix stretchability and interfacial adhesion. Subsequently, ethanol exchange reduced solvent impact and led to a compact network that limited surface exposure of ionic and hydrophilic groups, resulting in nonstick, robust for convenient storage. Finally, upon contacting with water, the network demonstrates rehydration, resulting in favorable adhesion, biocompatibility, and conductivity. The proposed PHEAA-NaSS/W gels can stably and reliably capture joint motion and electrophysiological signals. Furthermore, this uncomplicated gel preparation method is also applicable to other electrolyte monomers.

2-N, 6-O sulfated chitosan evokes periosteal stem cells for bone regeneration.

Musculoskeletal injuries and bone defects represent a significant clinical challenge, necessitating innovative approaches for effective bone tissue regeneration. In this study, we investigated the potential of harnessing periosteal stem cells (PSCs) and glycosaminoglycan (GAG)-mimicking materials for in situ bone regeneration. Our findings demonstrated that the introduction of 2-N, 6-O sulfated chitosan (26SCS), a GAG-like polysaccharide, enriched PSCs and promoted robust osteogenesis at the defect area. Mechanistically, 26SCS amplifies the biological effect of endogenous platelet-derived growth factor-BB (PDGF-BB) through enhancing the interaction between PDGF-BB and its receptor PDGFRß abundantly expressed on PSCs, resulting in strengthened PSC proliferation and osteogenic differentiation. As a result, 26SCS effectively improved bone defect repair, even in an osteoporotic mouse model with lowered PDGF-BB level and diminished regenerative potential. Our findings suggested the significant potential of GAG-like biomaterials in regulating PSC behavior, which holds great promise for addressing osteoporotic bone defect repair in future applications.

Electro-Sorting Create Heterogeneity: Constructing A Multifunctional Janus Film with Integrated Compositional and Microstructural Gradients for Guided Bone Regeneration.

Biology remains the envy of flexible soft matter fabrication because it can satisfy multiple functional needs by organizing a small set of proteins and polysaccharides into hierarchical systems with controlled heterogeneity in composition and microstructure. Here, it is reported that controlled, mild electronic inputs (<10 V; <20 min) induce a homogeneous gelatin-chitosan mixture to undergo sorting and bottom-up self-assembly into a Janus film with compositional gradient (i.e., from chitosan-enriched layer to chitosan/gelatin-contained layer) and tunable dense-porous gradient microstructures (e.g., porosity, pore size, and ratio of dense to porous layers). This Janus film performs is shown multiple functions for guided bone regeneration: the integration of compositional and microstructural features confers flexible mechanics, asymmetric properties for interfacial wettability, molecular transport (directional growth factor release), and cellular responses (prevents fibroblast infiltration but promotes osteoblast growth and differentiation). Overall, this work demonstrates the versatility of electrofabrication for the customized manufacturing of functional gradient soft matter.

Programmable Electro-Assembly of Collagen: Constructing Porous Janus Films with Customized Dual Signals for Immunomodulation and Tissue Regeneration in Periodontitis Treatment.

Currently available guided bone regeneration (GBR) films lack active immunomodulation and sufficient osteogenic ability- in the treatment of periodontitis, leading to unsatisfactory treatment outcomes. Challenges remain in developing simple, rapid, and programmable manufacturing methods for constructing bioactive GBR films with tailored biofunctional compositions and microstructures. Herein, the controlled electroassembly of collagen under the salt effect is reported, which enables the construction of porous films with precisely tunable porous structures (i.e., porosity and pore size). In particular, bioactive salt species such as the anti-inflammatory drug diclofenac sodium (DS) can induce and customize porous structures while enabling the loading of bioactive salts and their gradual release. Sequential electro-assembly under pre-programmed salt conditions enables the manufacture of a Janus composite film with a dense and DS-containing porous layer capable of multiple functions in periodontitis treatment, which provides mechanical support, guides fibrous tissue growth, and acts as a barrier preventing its penetration into bone defects. The DS-containing porous layer delivers dual bio-signals through its morphology and the released DS, inhibiting inflammation and promoting osteogenesis. Overall, this study demonstrates the potential of electrofabrication as a customized manufacturing platform for the programmable assembly of collagen for tailored functions to adapt to specific needs in regenerative medicine.

Senescence-Targeted and NAD+-Dependent SIRT1-Activated Nanoplatform to Counteract Stem Cell Senescence for Promoting Aged Bone Regeneration.

Age-related bone defects are a leading cause of disability and mortality in elderly individuals, and targeted therapy to delay the senescence of bone marrow-derived mesenchymal stem cells (MSCs) has emerged as a promising strategy to rejuvenate bone regeneration in aged scenarios. More specifically, activating the nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin 1 (SIRT1) pathway is demonstrated to effectively counteract MSC senescence and thus promote osteogenesis. Herein, based on an inventively identified senescent MSC-specific surface marker Kremen1, a senescence-targeted and NAD+ dependent SIRT1 activated nanoplatform is fabricated with a dual delivery of resveratrol (RSV) (SIRT1 promoter) and nicotinamide riboside (NR, NAD+ precursor). This targeting nanoplatform exhibits a strong affinity for senescent MSCs through conjugation with anti-Kremen1 antibodies and enables specifically responsive release of NR and RSV in lysosomes via senescence-associated ß-galactosidase-stimulated enzymatic hydrolysis of the hydrophilic chain. Furthermore, this nanoplatform performs well in promoting aged bone formation both in vitro and in vivo by boosting NAD+, activating SIRT1, and delaying MSC senescence. For the first time, a novel senescent MSC-specific surface marker is identified and aged bone repair is rejuvenated by delaying senescence of MSCs using an active targeting platform. This discovery opens up new insights for nanotherapeutics aimed at age-related diseases.