Neutrophil-mediated Nanozyme Delivery System for Acute Kidney Injury Therapy.

Reactive oxygen species (ROS) scavenging of nanozymes toward acute kidney injury (AKI) is a current promising strategy, however, the glomerular filtration barrier (GFB) limits their application for treating kidney related diseases. Here, a neutrophil-mediated delivery system able to hijack neutrophil to transport nanozyme-loaded cRGD-liposomes to inflamed kidney for AKI treatment by cRGD targeting integrin αvß1 is reported. The neutrophil-mediated nanozyme delivery system was demonstrated great antioxidant and anti-apoptosis ability in HK-2 and NRK-52E cell lines. Moreover, in ischemia-reperfusion (I/R) induced AKI mice, a single dose of LM@cRGD-LPs 12 h post-ischemia significantly reduced renal function indicators, alleviated renal pathological changes and inhibited apoptosis of renal tubular cells and the expression of renal tubular injured marker, thus remarkably reducing the damage of AKI. Mechanistically, the treatment of LM@cRGD-LPs markedly inhibited the process of Nrf2 to the nucleus and reduced the expression of the downstream HO-1, achieved a 99.51% increase in renal tissue Nrf2 levels and an 86.31% decrease in HO-1 levels after LM@cRGD-LPs treatment. In short, the strategy of neutrophil-mediated nanozyme delivery system hold great promise as a potential therapy for AKI or other inflammatory diseases. This article is protected by copyright. All rights reserved.

Reactive Microneedle Patches with Antibacterial and Dead Bacteria-Trapping Abilities for Skin Infection Treatment.

Bacterial skin infections are highly prevalent and pose a significant public health threat. Current strategies are primarily focused on the inhibition of bacterial activation while disregarding the excessive inflammation induced by dead bacteria remaining in the body and the effect of the acidic microenvironment during therapy. In this study, a novel dual-functional MgB2 microparticles integrated microneedle (MgB2 MN) patch is presented to kill bacteria and eliminate dead bacteria for skin infection management. The MgB2 microparticles not only can produce a local alkaline microenvironment to promote the proliferation and migration of fibroblasts and keratinocytes, but also achieve >5 log bacterial inactivation. Besides, the MgB2 microparticles effectively mitigate dead bacteria-induced inflammation through interaction with lipopolysaccharide (LPS). With the incorporation of these MgB2 microparticles, the resultant MgB2 MN patches effectively kill bacteria and capture dead bacteria, thereby mitigating these bacteria-induced inflammation. Therefore, the MgB2 MN patches show good therapeutic efficacy in managing animal bacterial skin infections, including abscesses and wounds. These results indicate that reactive metal borides-integrated microneedle patches hold great promise for the treatment of clinical skin infections.

Engineered mRNA Delivery Systems for Biomedical Applications.

Messenger RNA (mRNA)-based therapeutic strategies have shown remarkable promise in preventing and treating a staggering range of diseases. Optimizing the structure and delivery system of engineered mRNA has greatly improved its stability, immunogenicity, and protein expression levels, which has led to a wider range of uses for mRNA therapeutics. Herein, a thorough analysis of the optimization strategies used in the structure of mRNA is first provided and delivery systems are described in great detail. Furthermore, the latest advancements in biomedical engineering for mRNA technology, including its applications in combatting infectious diseases, treating cancer, providing protein replacement therapy, conducting gene editing, and more, are summarized. Lastly, a perspective on forthcoming challenges and prospects concerning the advancement of mRNA therapeutics is offered. Despite these challenges, mRNA-based therapeutics remain promising, with the potential to revolutionize disease treatment and contribute to significant advancements in the biomedical field.

A Biomimetic Cardiac Fibrosis-on-a-Chip as a Visible Disease Model for Evaluating Mesenchymal Stem Cell-Derived Exosome Therapy.

Cardiac fibrosis acts as a serious worldwide health issue due to its prevalence in numerous forms of cardiac disease and its essential link to cardiac failure. Considering the efficiency of stem cell therapy for cardiac fibrosis, great efforts have been dedicated to developing accurate models for investigating their underlying therapeutic mechanisms. Herein we present an elaborate biomimetic cardiac fibrosis-on-a-chip based on Janus structural color film (SCF) to provide microphysiological visuals for stem cell therapeutic studies. By coculturing cardiomyocytes (CMs) and cardiac fibroblasts (FBs) on Janus SCF with fibrosis induction, the chip can recreate physiological intercellular crosstalk within the fibrotic microenvironment, elucidating the physiological alterations of fibrotic hearts. In particular, the Janus structural color film possesses superior perceptual capabilities for capturing and responding to a weak cardiac force, demonstrating synchronized structural color shifts. Based on these features, we have not only explored the dynamic relationship between color mapping and the evaluated disease phenotype but also demonstrated the self-reporting capacity of the cardiac fibrosis-on-a-chip for the assessment of mesenchymal stem cell-derived exosome therapy. These features suggest that such a chip can potentially facilitate the evolution of precision medicine strategies and create a protocol for preclinical cardiac drug screening.

Environmental impacts of carbon fiber production and decarbonization performance in wind turbine blades.

The application of carbon fiber in the wind power industry is of great interest in declining CO2 emissions but the carbon fiber manufacturing process is still a long way heading cleaner production. Since little to no information clarifies the dual effects from carbon fiber production to application, this study carried out a life cycle assessment (LCA) to recognize the environmental performances of polyacrylonitrile (PAN)-based carbon fiber production and explore the decarbonization effects of carbon fiber application in wind turbine blades. Based on on-site data from a leading carbon fiber production chain in China, potential environmental impacts of carbon fiber production predominantly originated from the precursor spinning stage (accounted for 13-91%). Fossil depletion (20.24 kg oil eq.), climate change (67.79 kg CO2 eq.), terrestrial ecotoxicity (165.63 kg 1,4-DCB eq.) and photochemical ozone formation (0.14 kg NOx eq.) were the four noteworthy areas to improve the sustainable development. Different scenarios in energy and advanced technology were set to explore the potential improvement of the environmental performance of carbon fiber products. Energy structure (wind power) can improve an average of 22.58% environmental benefit compared with the background scenarios. Regarding the decarbonization effects, the energy payback time and the carbon payback time were estimated to be 0.73 and 0.37 months respectively. Therefore, carbon fiber is a trustworthy material in the strategy to achieve sustainable development from a life cycle perspective.

CXCR4-Expressing Mesenchymal Stem Cells Derived Nanovesicles for Rheumatoid Arthritis Treatment.

Cell membrane camouflage technology, which a demonstrated value for the bionic replication of natural cell membrane properties, is an active area of ongoing research readily applicable to nanomedicine. How to realize immune evasion, slow down the clearance from the body, and improve targeting are still worth great efforts for this technology. Herein, novel cell membrane-mimicked nanovesicles from genetically engineered mesenchymal stem cells (MSCs) are presented as a potential anti-inflammatory platform for rheumatoid arthritis (RA) management. Utilizing the synthetic biology approach, the biomimetic nanoparticles are constructed by fusing C-X-C motif chemokine receptor4 (CXCR4)-anchored MSC membranes onto drug-loaded polymeric cores (MCPNs), which make them ideal decoys of stromal cell-derived factor-1 (SDF-1)-targeted arthritis. These resulting nanocomplexes function to escape from the immune system and enhance accumulation in the established inflamed joints via the CXCR4/SDF-1 chemotactic signal axis, thereby achieving an affinity to activated macrophages and synovial fibroblasts. It is further demonstrated that the MCPNs can significantly suppress synovial inflammation and relieve pathological conditions with favorable safety properties in collagen-induced arthritis mice. These findings indicate the clinical value of MCPNs as biomimetic nanodrugs for RA therapy and related diseases.

Biomimetic liposomes hybrid with erythrocyte membrane modulate dendritic cells to ameliorate systemic lupus erythematosus.

Dendritic cells (DCs)-based immunotherapy has shown immense promise in systemic lupus erythematosus (SLE) treatment. However, existing carrier strategies such as polymers, liposomes, and polypeptides, are difficult to achieve active targeting to DCs due to their intricate interaction with biological systems. Since DCs represent a class of phagocytes responsible for the removal of senescent or damaged erythrocytes, we hypothesize that hybrid vesicles containing erythrocytes membrane components could be presented to be potent drug carriers to target DCs specifically. Herein, inspired by the cell membrane fusion technique, we develop hybrid biomimetic liposomes (R-Lipo) by fusing natural erythrocyte membrane vesicles and artificial liposomes for DCs-targeted SLE therapy. The resultant R-Lipo exhibited excellent biocompatibility and was shown to be effectively internalized by DCs both in vitro and in vivo. Using an immunosuppressant, mycophenolic acid (MPA), as the model drug, MPA-loaded R-Lipo powerfully suppressed DCs maturation and efficiently controlled the duration of lupus nephritis without apparent side effects. Our findings provide a safe, effective, and easy-to-prepare biomimetic vesicle platform for the treatment of SLE and other DC-associated diseases.

Bioinspired Adaptable Indwelling Microneedles for Treatment of Diabetic Ulcers.

Microneedles provide an effective strategy for transdermal drug delivery. Many endeavors have been devoted to developing smart microneedles that can respond to and interact with pathophysiological environments. Here, novel bioinspired adaptable indwelling microneedles with therapeutic exosome encapsulation are presented for diabetic wound healing by a combined fabrication strategy of template replication and 3D transfer printing. Such microneedles are composed of mesenchymal stem cell (MSC)-exosomes-encapsulated adjustable poly(vinyl alcohol) (PVA) hydrogel needle tips and detachable 3M medical tape supporting substrate. As the mechanical strength of the PVA hydrogel is ionically responsive due to Hofmeister effects, the hardness of the resultant microneedle tips can be upregulated by sulfate ions to ensure skin penetration and be softened by nitrate ions after tip-substrate detachment to adapt to the surrounding tissue and release exosomes. Because the MSC-exosomes can effectively activate fibroblasts, vascular endothelial cells, and macrophages, the indwelling microneedles are demonstrated with the function of promoting tissue regeneration and diabetic wound healing in full-thickness cutaneous wounds of diabetic rat models. These features indicate that the bioinspired adaptable indwelling microneedles are with practical values and clinical prospects in tissue and wound regeneration.

Mesenchymal Stem Cell Exosomes Encapsulated Oral Microcapsules for Acute Colitis Treatment.

Mesenchymal stem cells derived exosomes (MSC-exos) exhibit an intrinsic and directed efficiency for multiple diseases, while their versatile and effective delivery to the target site is still a challenge. Herein, inspired by the acids and enzymes resistant property of sealing gelatin capsules, novel MSC-exo-encapsulated oral microcapsules are presented for colitis treatment. Based on a microfluidic electrospray technique, MSC-exos are first encapsulated in sodium alginate (SA) hydrogel microspheres with sustainable bioactivity. The resultant SA microspheres are then coated with a middle gelatin layer to protect MSC-exos from degradation. Especially, with an enteric coating-Eudragit FS30D on the outer layer, the resistance of the microcapsules in gastric juice is further enhanced. The prepared microcapsules maintain the stability and bioactivity of the MSC-exos during storage, protect them from the harsh conditions in the gastrointestinal tract, and enable the release of actives in the suitable sites for exerting their biological functions. In addition, these MSC-exos encapsulated microcapsules reduce the proinflammatory cytokines levels of inflammatory macrophages and impaired colonic epithelial cells, which exhibit superior damage repair ability in injured colon sites. Thus, it is believed that the proposed oral MSC-exos encapsulated microcapsules are valuable for many practically clinical treatments.

Polydopamine Decorated Microneedles with Fe-MSC-Derived Nanovesicles Encapsulation for Wound Healing.

Wound dressing with the capacities of antioxidation, antiinflammation, and efficient angiogenesis induction is expected for effectively promoting wound healing. Herein, a novel core-shell hyaluronic acid (HA) microneedle (MN) patch with ferrum-mesenchymal stem cell-derived artificial nanovesicles (Fe-MSC-NVs) and polydopamine nanoparticles (PDA NPs) encapsulated in the needle tips is presented for wound healing. Fe-MSC-NVs containing multifunctional therapeutic cytokines are encapsulated in the inner HA core of the MN tips for accelerating angiogenesis. The PDA NPs are encapsulated in the outer methacrylated hyaluronic acid (HAMA) shell of the MN tips to overcome the adverse impacts from reactive oxygen species (ROS)-derived oxidative stress. With the gradual degradation of HAMA patch tips in the skin, the PDA NPs are sustainably released at the lesion to suppress the ROS-induced inflammation reaction, while the Fe-MSC-NVs significantly increase the migration, proliferation, and tube formation of human umbilical vein endothelial cells (HUVEC). More attractively, the combination of PDA NPs and Fe-MSC-NVs further promotes M2 macrophage polarization, thereby suppressing wound inflammation. Through in vivo experiment, the Fe-MSC-NVs/PDA MN patch shows an excellent effect for diabetic wound healing. These features of antioxidation, antiinflammation, and pro-angiogenesis indicate the proposed composite core-shell MN patch is valuable for clinical wound healing applications.

Denatured corona proteins mediate the intracellular bioactivities of nanoparticles via the unfolded protein response.

Biomolecular corona formed on nanoparticles (NPs) influences the latter's in vivo biological effects. Nanomaterials with different physicochemical properties exert similar adverse effects, such as cytotoxicity, suggesting the existence of ubiquitous signals during various corona formations that mediate common and fundamental cellular events. Here, we discover the involvement of the unfolded protein response (UPR) and recruited chaperones in the corona. Specially, heat shock protein 90 kDa α class B member 1 (Hsp90ab1) is abundantly enriched in the corona, accompanied by substantial aggregation of misfolded protein on particles intracellularly. Further analysis reveals the particulate matter 2.5 (PM2.5) and metal-containing particles are more capable of denaturing proteins. The recruited Hsp90ab1 activates diverse NPs' pathological behaviour by heat stress response (HSR), which were significantly reversed by geldanamycin (GA), the inhibitor of Hsp90ab1. Murine lung inflammation induced by PM2.5 and iron oxide NPs (Fe3O4NPs) is suppressed by GA, highlighting that Hsp90ab1-mediated UPR is a potential target for the treatment of environmental pollution-related illnesses. Based on our findings, the UPR and Hsp90ab1 presented in the corona of particles initiate fundamental intracellular reactions that lead to common pathological outcomes, which may provide new insights for understanding nanotoxicity and designing therapeutic approaches for diseases associated with environmental pollution.

Bio-inspired adhesive porous particles with human MSCs encapsulation for systemic lupus erythematosus treatment.

Mesenchymal stem cells (MSCs) therapy is a promising treatment for Systemic lupus erythematosus (SLE) patients. However, this method is encumbered by suboptimal phenotype of MSCs used in clinical settings, and a short in vivo persistence time. Herein, inspired by the natural microstructure of the sand tower worm nest, we proposed novel adhesive porous particles with human MSCs encapsulation via microfluidic electrospray technology for SLE treatment. The porous microparticles were formed by immediate gelation reaction between sodium alginate (ALG) and poly-d-lysine (PDL), and then sacrificed polyethylene oxide (PEO) to form the pores. The resultant microparticles could protect MSCs from immune cells while maintain their immune modulating functions, and achieve rapid exchange of nutrients from the body. In addition, owing to the electrostatic adsorption and covalent bonding between PDL and tissues, the porous microparticles could adhere to the bowel surfaces tightly after intraperitoneal injection. Through in vivo imaging system (IVIS) methods and in vivo study, it was demonstrated that the MSCs-encapsulated porous adhesive microparticles could significantly increase the cellular half-life, turn activated inflammatory macrophages into an anti-inflammatory profile, and ameliorate disease progression in MRL/lpr mice. Thus, the MSCs-encapsulated porous microparticles showed distinctive functions in chronic SLE treatment, with additional potential to be used in a variety of biomedical applications.

Transforming the spleen into a liver-like organ in vivo.

Regenerating human organs remains an unmet medical challenge. Suitable transplants are scarce, while engineered tissues have a long way to go toward clinical use. Here, we demonstrate a different strategy that successfully transformed an existing, functionally dispensable organ to regenerate another functionally vital one in the body. Specifically, we injected a tumor extract into the mouse spleen to remodel its tissue structure into an immunosuppressive and proregenerative microenvironment. We implanted autologous, allogeneic, or xenogeneic liver cells (either primary or immortalized), which survived and proliferated in the remodeled spleen, without exerting adverse responses. Notably, the allografted primary liver cells exerted typical hepatic functions to rescue the host mice from severe liver damages including 90% hepatectomy. Our approach shows its competence in overcoming the key challenges in tissue regeneration, including insufficient transplants, immune rejection, and poor vascularization. It may be ready for translation into new therapies to regenerate large, complex human tissue/organs.

Accelerated wound healing in diabetes by reprogramming the macrophages with particle-induced clustering of the mannose receptors.

The rate-limiting step in cutaneous wound healing, namely, the transition from inflammation to cell proliferation, depends on the high plasticity of macrophages to prevent inflammation in the wound tissues in a timely manner. Thus, strategies that reprogram inflammatory macrophages may improve the healing of poor wounds, particularly in the aged skin of individuals with diabetes or other chronic diseases. As shown in our previous study, KGM-modified SiO2 nanoparticles (KSiNPs) effectively activate macrophages to differentiate into the M2-type phenotype by inducing mannose receptor (MR) clustering on the cell surface. Here, we assess whether KSiNPs accelerate wound healing following acute or chronic skin injury. Using a full-thickness excision model in either diabetic mice or healthy mice, the wounds treated with KSiNPs displayed a dramatically increased closure rate and collagen production, along with decreased inflammation and increased angiogenesis in the regenerating tissues. Furthermore, KSiNPs induced the formation of M2-like macrophages by clustering MR on the cells. Accordingly, the cytokines produced by the KSiNP-treated macrophages were capable of inducing fibroblast proliferation and subsequent secretion of extracellular matrix (ECM). Based on these results, KSiNPs display great potential as an effective therapeutic approach for cutaneous wounds by effectively suppressing excessive or persistent inflammation and fibrosis.

Growing Trans-Species Islets in Tumor Extract-Remodeled Testicles.

Although pancreatic islet transplantation holds promise for the treatment of type I diabetes, its application has been significantly hampered by transplant rejection. Here, an approach is demonstrated to support trans-species islet beta cells from a rat to grow and function in the body of a mouse host while overcoming graft rejection. This approach, which builds on remodeling of the mouse testicle by local injection of a tumor homogenate, establishes an immunosuppressive and proregenerative niche in the testicle. This remodeling proves necessary and effective in shaping the testicle into a unique site to accommodate xenograft cells. Rat pancreatic beta cells-from both the insulinoma (cancer cells) and pancreatic islet (normal tissue)-survive, grow, and form a desirable morphology in the remodeled mouse testicle. Notably, when hyperglycemia is induced in the host body, these xenografts secrete insulin to regulate the blood glucose level in mice for as long as 72 days. Furthermore, no graft rejection, acute inflammation, or safety risks are observed throughout the study. In summary, it is demonstrated that the growth of xenogeneic insulinoma cells in a mouse testicle might serve as an alternative approach for islet transplantation.

A novel fluorinated triazole derivative suppresses macrophage activation and alleviates experimental colitis via a Twist1-dependent pathway.

Hyperactivated macrophages play a key role in the initiation and perpetuation of mucosal inflammation in Crohn's disease (CD). Increasing evidence suggests that the basic helix-loop-helix (bHLH) repressor Twist1 can suppress activation of nuclear factor-κB (NF-κB) and the subsequent production of TNF-α, which are both essential elements of macrophage activation. Thus, developing novel therapeutic strategies to enhance Twist1 expression and to inhibit macrophage activation may be beneficial for CD treatment. In the present study, a series of trifluoroethyl thiazolo[3,2-b][1,2,4]triazole derivatives were used to investigate their potential anti-inflammatory activities and the underlying mechanism. In a biological activity screen, compound 7# (Thiazolo[3,2-b][1,2,4]triazole-5-methanamine, 6-phenyl-α-(trifluoromethyl)-, (αR)-, TT-TFM) suppressed the activation of macrophages. Consistent with the in vitro data, TT-TFM protected against 2,4,6-trinitrobenzene sulfonic acid (TNBS), dextran sulfate sodium (DSS)-induced acute colitis and IL-10 knockout (KO) chronic colitis, as judged by body weight changes and colonic pathological damage. A mechanistic study based on microarray analysis and gene interference experiments indicated that TT-TFM exerted anti-inflammatory effects by enhancing Twist1 expression and subsequently blocking the NF-κB/TNF-α pathway. In addition, pretreatment with lentiviruses encoding shRNA targeting Twist1 could abolish the therapeutic effect of TT-TFM in TNBS colitis. Ultimately, TT-TFM showed anti-colitis activity by reducing NF-κB activation and the TNF-α level by promoting Twist1 expression; thus, TT-TFM may offer a therapeutic strategy for CD patients.

Producing anti-inflammatory macrophages by nanoparticle-triggered clustering of mannose receptors.

Macrophages are highly plastic cells that can either mediate or suppress inflammation, depending on their cellular phenotype and cytokine secretion. Inducing macrophages from an inflammatory ('M1') to anti-inflammatory ('M2') phenotype has significant implications for the treatment of inflammatory diseases and regeneration of injured tissues. Although certain cytokines, such as interleukin-4 and -13, are known to induce this phenotypic switch, their therapeutic use in vivo has both safety and efficacy concerns. Here, we demonstrate an alternative approach to change macrophage phenotype from M1 to M2, through inducing the clustering of mannose receptors (MR) on the cell surface, by using carbohydrate-presenting substrates. We prepared and screened glucomannan-decorated silicon oxide of different sizes ranging from 10 to 1000 nm, and identified one type (KSiNP30) that could potently induce MR clustering on macrophages and thereby stimulated the cells into an M2 phenotype - as an unexpected consequence of MR activation. Further administration of KSiNP30 in a murine model of inflammatory bowel disease efficiently alleviated the colitis symptoms, indicating the translational potential of our finding for therapeutic applications. In summary, we report for the first time an approach to modulate cellular immune responses by manipulating the assembly of cell-surface receptors, without the aid of cytokines. Our approach may provide insights for the development of new anti-inflammatory therapies.

Probiotics protect mice from CoCrMo particles-induced osteolysis.

Wear particle-induced inflammatory osteolysis is the primary cause of aseptic loosening, which is the most common reason for total hip arthroplasty (THA) failure in the med- and long term. Recent studies have suggested an important role of gut microbiota (GM) in modulating the host metabolism and immune system, leading to alterations in bone mass. Probiotic bacteria administered in adequate amounts can alter the composition of GM and confer health benefits to the host. Given the inflammatory osteolysis that occurs in wear debris-induced prosthesis loosening, we examined whether the probiotic Lactobacillus casei could reduce osteolysis in a mouse calvarial resorption model. In this study, L. casei markedly protected mice from CoCrMo particles (CoPs)-induced osteolysis. Osteoclast gene markers and the number of osteoclasts were significantly decreased in L. casei-treated mice. Probiotic treatment decreased the M1-like macrophage phenotype indicated by downregulation of tumor necrosis factor α (TNF-α), interleukin (IL)-6 and inducible nitric oxide synthase (iNOS) and increased the M2-like macrophage phenotype indicated by upregulation of IL-4, IL-10 and arginase. Collectively, these results indicated that the L. casei treatment modulated the immune status and suppressed wear particle-induced osteolysis in vivo. Thus, probiotic treatment may represent a potential preventive and therapeutic approach to reduced wear debris-induced osteolysis.

Specifically Formed Corona on Silica Nanoparticles Enhances Transforming Growth Factor ß1 Activity in Triggering Lung Fibrosis.

A corona is a layer of macromolecules formed on a nanoparticle surface in vivo. It can substantially change the biological identity of nanomaterials and possibly trigger adverse responses from the body tissues. Dissecting the role of the corona in the development of a particular disease may provide profound insights for understanding toxicity of nanomaterials in general. In our present study, we explored the capability of different silica nanoparticles (SiNPs) to induce silicosis in the mouse lung and analyzed the composition of coronas formed on these particles. We found that SiNPs of certain size and surface chemistry could specifically recruit transforming growth factor ß1 (TGF-ß1) into their corona, which subsequently induces the development of lung fibrosis. Once embedded into the corona on SiNPs, TGF-ß1 was remarkably more stable than in its free form, and its fibrosis-triggering activity was significantly prolonged. Our study meaningfully demonstrates that a specific corona component on a certain nanoparticle could initiate a particular pathogenic process in a clinically relevant disease model. Our findings may shed light on the understanding of molecular mechanisms of human health risks correlated with exposure to small-scale substances.

Expression of XBP1s in fibroblasts is critical for TiAl6 V4 particle-induced RANKL expression and osteolysis.

Wear particle-induced osteolysis is a major cause of aseptic loosening, which is one of the most common reasons for total hip arthroplasty (THA) failure. Previous studies have shown that the expression of Receptor activation of nuclear factor (NF)-kB (RANKL) by fibroblasts in periprosthetic membrane played a crucial role in wear particle-induced osteolysis. However, the underlying mechanism of RANKL expression remains largely unknown. In the present study, we investigated the effect of TiAl6 V4 particle (TiPs)-induced XBP1s (spliced form of X-box binding protein 1) on RANKL expression and osteoclastogenesis both in vitro and in vivo. The levels of XBP1s in peri-implant membrane, animal models, and TiPs-stimulated fibroblasts were determined by western blots. To assess the effect of XBP1s on RANKL expression, fibroblasts were treated with both a small interfering RNA (siRNA) and an inhibitor of XBP1 prior to exposure to TiPs. The effect of XBP1s on osteoclasts formation was determined by tartrate-resistant acid phosphatase (TRAP) staining in vitro osteoclastogenesis assay and in animal models. The resorption of bone was assessed by micro-computed tomography (micro-CT) with three-dimensional reconstruction. Our results demonstrated that XBP1s was activated in periprosthetic membrane, mouse calvaria models, and TiPs-stimulated human synovial fibroblasts. Further, inhibition of XBP1s decreased the expression of RANKL and osteoclasts formation in vitro. In mouse calvaria models, both of the osteoclastogenesis and osteolysis were inhibited XBP1s inhibitor. Our results suggested that XBP1s mediated TiPs-induced of RANKL expression in fibroblasts, and down regulating XBP1s may represent a potential therapy for wear particle-induced osteolysis. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:752-759, 2017.