As a chronic inflammatory disease characterized by periodontal tissue destruction, periodontitis has a pathogenesis that remains incompletely understood. This study aimed to investigate the expression of upregulated vanin-2 (VNN2) in exosomes derived from dental pulp stem cells (DPSCs) and its effects on the function of periodontal ligament stem cells (PDLSCs) and the progression of periodontitis. A total of 35 patients with periodontitis and 35 healthy individuals were enrolled for gingival tissue sample collection. DPSC-EXO-VNN2 was cultured with a 3D system and isolated by ultracentrifugation. The samples were then subjected to nanoparticle tracking analysis (NTA), western blot and transmission electron microscopy (TEM). In vitro, PDLSCs were treated with DPSC- EXO-VNN2 and LPS, and the expression of IL-6 and TNF-α and their osteogenic potential were evaluated. Furthermore, in vivo, experimental periodontitis was induced in rats, which were then divided into two groups and treated with either DPSC-EXO-VNN2 or PBS. The maxillae were subsequently collected for histological staining and micro-CT analysis. VNN2 was upregulated in periodontitis according to dataset analysis, western blot and immunofluorescence (P < 0.05). Higher expression levels of VNN2 were associated with greater periodontal parameters PD and CAL (P < 0.05). The production of DPSC-EXO in the 3D culture system surpassed that in the 2D system. In vitro, PDLSCs internalized 3D-DPSC-EXO-VNN2, which increased LPS-induced IL-6 and TNF-α production while reducing osteogenic differentiation, as shown by decreased ALP activity and mineralization. In vivo, DPSC-EXO-VNN2 administration worsened alveolar bone loss, as micro-CT revealed a significantly lower bone volume fraction (P < 0.01) than did the control treatment. This study reveals for the first time that DPSC-EXO-VNN2 participates in the progression of periodontitis by regulating the inflammatory response and osteogenic differentiation ability of PDLSCs. Future research may further explore the potential application of targeting VNN2 in treating periodontitis.

Osteonecrosis of the femoral head (ONFH) is a debilitating condition often leading to joint collapse. While corticosteroids use and alcohol consumption are known risk factors, the pathophysiology, especially in idiopathic cases, which account for one-third population, remains unclear. This study aimed to investigate the potential role of human cytomegalovirus (HCMV) reactivation in the pathogenesis of ONFH, focusing on its presence, distribution, and reactivation status. Blood and femoral head samples were obtained from ONFH patients and fracture controls. Human cytomegalovirus exposure was assessed through serology and viral DNA quantification, and reactivation was confirmed by gB immunohistochemistry and IE-1 mRNA RT-qPCR. Tissue samples from different regions of the femoral head (necrotic, transitional, and healthy zones) were analyzed for viral content, reactivation, and localization. Results showed significantly higher HCMV DNA levels in necrotic and transitional zones of ONFH, strongly correlated with lesion volume. Furthermore, gB localization was predominantly found in the microvascular structures, such as small vessels and capillaries, suggesting that HCMV reactivation may contribute to microvascular damage and ischemia. IE-1 transcripts, markers of viral reactivation, further confirmed reactivation. Notably, HCMV reactivation was observed across all ONFH etiologies-corticosteroid-related, alcohol-related, and idiopathic-indicating its broad involvement in ONFH progression. This study provides the first clinical evidence linking HCMV reactivation to ONFH, offering potential therapeutic avenues, including antiviral treatments, to address this condition.

[This retracts the article DOI: 10.1016/j.heliyon.2024.e41275.].

Arsenic trioxide (As2O3) has achieved groundbreaking success in the treatment of acute promyelocytic leukemia (APL). However, its toxic side effects seriously limit its therapeutic application in the treatment of solid tumors. To detoxify the severe side effects of arsenic, herein we synthesized innovative 2D ultrathin As2Se3 nanosheets (As2Se3 NSs) with synergistic photothermal-triggered immunotherapy effects. As2Se3 NSs are biocompatible and biodegradable under physiological conditions and can release As(III) and Se(0). Furthermore, selenium increases the immunomodulatory efficacy of arsenic treatments, facilitating reprogramming of the tumor microenvironment by As2Se3 NSs by enhancing the infiltration of natural killer cells and effector tumor-specific CD8+ T cells. The synergistic combination of photothermal therapy and immunotherapy driven by As2Se3 NSs via a simple but effective all-in-one strategy achieved efficient anticancer effects, addressing the key limitations of As2O3 for solid tumor treatment. This work demonstrates not only the great potential of selenium for detoxifying arsenic but also the application of 2D As2Se3 nanosheets for cancer therapy.

Background & Aims: Ectopic liver regeneration in the spleen is a promising alternative to organ transplantation for treating liver failure. To accommodate transplanted liver cells, the splenic tissue must undergo structural changes to increase extracellular matrix content, demanding a safe and efficient approach for tissue remodelling. Methods: We synthesised sulphated hyaluronic acid (sHA) with an affinity for the latent complex of transforming growth factor -8 (TGF-8) and cross -linked it into a gel network (sHA-X) via click chemistry. We injected this glycan into the spleens of mice to induce splenic tissue remodelling via supraphysiological activation of endogenous TGF-8. Results: sHA-X efficiently bound to the abundant latent TGF-8 in the spleen. It provided the molecular force to liberate the active TGF-8 dimers from their latent complex, mimicking the 'bind -and -pull' mechanism required for physiological activation of TGF-8 and reshaping the splenic tissue to support liver cell growth. Hepatocytes transplanted into the remodelled spleen developed into liver tissue with sufficient volume to rescue animals with a metabolic liver disorder ( Fah -/- transgenic model) or following 90% hepatectomy, with no adverse effects observed and no additional drugs required. Conclusion: Our findings highlight the efficacy and translational potential of using sHA-X to remodel a specific organ by mechanically activating one single cytokine, representing a novel strategy for the design of biomaterials-based therapies for organ regeneration. (c) 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Eliminating biofilms from infected tissue presents one of the most challenging issues in clinical treatment of chronic wounds. In biofilms, the extracellular polymeric substances (EPS) form gel structures by electrostatic forces between macromolecules. We hypothesized that cationic polymers could induce the gel-to-sol phase transition of the network, leading to biofilms disruptions. We first validated this assumption by using polyethyleneimine (PEI) as a model molecule, and further synthesized two cationic dextrans with high biodegradability for in vitro and in vivo evaluation. All the cationic polymers could destruct Pseudomonas aeruginosa (P. aeruginosa) biofilms. Treating biofilm with cationic dextrans significantly enhanced the bacterial antibiotic sensitivity. When tested in a biofilm-presenting mouse wound healing model, the cationic dextrans efficiently controlled infection, and accelerated the healing process. Our findings suggest that devising cationic polymers to trigger phase transition of biofilm is an effective, straightforward, and perhaps generic strategy for anti-bacterial therapies.

Surgical removal of the thyroid gland (TG) for treating thyroid disorders leaves the patients on lifelong hormone replacement that partially compensates the physiological needs, but regenerating TG is challenging. Here, an approach is reported to regenerate TG within the spleen for fully restoring the thyroid's functions in mice, by transplanting thyroid tissue blocks to the spleen. Within 48 h, the transplanted tissue efficiently revascularizes, forming thyroid follicles similar to the native gland after 4 weeks. Structurally, the ectopically generated thyroid integrates with the surrounding splenic tissue while maintaining its integrity, separate from the lymphatic tissue. Functionally, it fully restores the native functions of the TG in hormone regulation in response to physiological stimuli, outperforming the established method of oral levothyroxine therapy in maintaining systemic homeostasis. The study demonstrates the full restoration of thyroid functions post-thyroidectomy by intrasplenic TG regeneration, providing fresh insights for designing novel therapies for thyroid-related disorders.

The formation of biomolecular condensates via liquid‒liquid phase separation (LLPS) is an advantageous strategy for cells to organize their subcellular compartments for diverse functions. Recent findings suggest that RNA or RNA-related LLPS techniques have potential for the development of new cellular regulation strategies. However, manipulating RNA LLPS in living cells has great challenges. Herein, we report that cationic polymers (CPs) have strong RNA LLPS-inducing activity. By introducing CPs into living cells or RNA solutions, significant RNA LLPS was verified through confocal imaging, turbidity assays, and fluorescence recovery after photobleaching (FRAP) tests. Among them, turbidity kinetics determinations indicated that the hydrophilic positively charged amino groups on the CPs play essential roles in RNA phase separation. Moreover, the LLPS induced by the cationic polymers dramatically changed the gene expression patterns in the cells. Interestingly, we found that TGFβ1 mRNA was highly encapsulated in the RNA droplets, which lowered the immunosuppressive capability of the tumor cells and triggered marked antitumor reactions in a mouse breast cancer model. Thus, we present here the CP-based modulation of RNA LLPS as a novel transcriptional manipulation method with potential for cancer immunotherapy drug development.

3D Printing Enabling three‐dimensional (3D) printing of polysaccharides, which are typically non‐printable, can exhibit their inherent bioactivities for better biomaterials design. In article number 2203236, Xiaoyan Sun, Lei Dong, Chunming Wang, and co‐workers develop a non‐solvent quenching (NSQ) strategy to print polysaccharides scaffolds with high fidelity to exert accurate immunomodulatory activities. It serves as a generic approach for printing polysaccharides without the need of chemical modification.

Although fine particulate matter (FPM) in air pollutants and tobacco smoke is recognized as a strong carcinogen and global threat to public health, its biological mechanism for inducing lung cancer remains unclear. Here, by investigating FPM’s bioactivities in lung carcinoma mice models, we discover that these particles promote lung tumor progression by inducing aberrant thickening of tissue matrix and hampering migration of antitumor immunocytes. Upon inhalation into lung tissue, these FPM particles abundantly adsorb peroxidasin (PXDN) – an enzyme mediating type IV collagen (Col IV) crosslinking – onto their surface. The adsorbed PXDN exerts abnormally high activity to crosslink Col IV via increasing the formation of sulfilimine bonds at the NC1 domain, leading to an overly dense matrix in the lung tissue. This disordered structure decreases the mobility of cytotoxic CD8+ T lymphocytes into the lung and consequently impairs the local immune surveillance, enabling the flourishing of nascent tumor cells. Meanwhile, inhibiting the activity of PXDN abolishes the tumor-promoting effect of FPM, indicating the key impact of aberrant PXDN activity on the tumorigenic process. In summary, our finding elucidates a new mechanism for FPM-induced lung tumorigenesis and identifies PXDN as a potential target for treatment or prevention of the FPM-relevant biological risks.

Biofilm-induced periodontitis is challenging for traditional anti-bacterial reagents. The dense extracellular polymeric substances (EPS) gel structures in biofilms restricted their penetration, inducing the latter’s limited biofilm elimination. Cationic dextrans might overcome the problem based on its superior capacity for biofilm disruptions by triggering the gel-to-sol phase transition of the EPS network. Aimed at this, first, we validated cationic dextrans could induce the phase transition of EPS in biofilms, including both the Gram-positive and Gram-negative bacteria, especially the P. gingivalis , a main periodontal anaerobic pathogen. Then, we confirmed the effects of cationic dextrans on removing both dental plaque biofilms and bacteria. Based on the satisfactory performance of cationic dextrans in vitro , effective in vivo treatment was achieved in a rat periodontal disease model, as demonstrated by significantly reduced dental plaque, suppressed alveolar bone loss, and alleviated periodontal inflammation. In summary, the study exploited an effective biomaterial to ameliorate periodontitis, with their powerful biofilm elimination potential. It’s promising to become a new broad-spectrum anti-biofilm agent for the treatment of periodontal disease.Funding Information: This study was funded by the National Natural Science Foundation of China (31971309, 32001069), the Natural Science Foundation of Jiangsu Province (BK20200318), and the Fundamental Research Funds for the Central Universities (021414380515). This study is also supported by the funds for the International Cooperation and Exchange of the Natural Science Foundation of China and the Science and Technology Development Fund (31961160701). Declaration of Interests: The authors have no competing financial interests to declare. Ethical Approval Statement: All experimental procedures involving animals were approved by the Institutional Animal Care and Use Committee of Nanjing University. The animal experiments involved in this study have complied with the stated ARRIVE Guidelines.

Abstract Tissue engineering (TE) is promising for the regeneration of failed organs. However, immune rejection, shortage of seed cells, and unintegrated blood vessels restrict the development and clinical application of TE. The last factor is the most challenging and intractable. Harnessing the mature blood vessel network in existing dispensable organs could be a powerful approach to effectively overcome the obstacles. After being remodeled to harbor an immunosuppressive and proregenerative niche, these potential target organs can be transformed into other organs with specific physiological functions, compensating the latter's failed native functions. Organ transformation, such as a hepatized spleen, represents an effective and encouraging TE strategy. In this review, we discuss the current development and obstacles of TE and its feasibility and superiority in organ transformation.

3D printing enables the customized design of implant structures for accurately regulating host responses. However, polysaccharides, as a major biomaterial category with versatile immune activities, are typically "non-printable" due to the collapse of their filaments extruded during printing. This challenge renders their potential as immunomodulatory scaffolds underexploited. Here, inspired by the quench hardening in metal processing, a nonsolvent quenching (NSQ) strategy is innovatively designed for the 3D printing of polysaccharides. Through rapid solvent exchanging, NSQ instantly induces surface hardening to strengthen the polysaccharide filaments upon extrusion, requiring neither chemical modification nor physical blending that alters the material properties. Tested with five polysaccharides with varying physicochemical properties, NSQ prints predesigned structures at organ-relevant scales and a long shelf-life over 3 months. Glucomannan scaffolds, fabricated via NSQ with different grid spacings (1.5 and 2.5 cm), induce distinct host responses upon murine subcutaneous implantation-from specific carbohydrate receptor activation to differential immunocytes accumulation and tissue matrix remodeling-as mechanistically validated in wild-type and Tlr2(-/-) knockout mice. Overall, NSQ as a facile and generic strategy is demonstrated to fabricate polysaccharide scaffolds with improved shape fidelity, thereby potentially unmasking their accurate immunomodulatory activities for future biomaterials design.

Osteoporosis poses substantial challenges for biomaterials implantation. New approaches to improve bone-implant integration should resolve the fundamental dilemma of inflammation-proper inflammation is required at early stages but should be suppressed later for better healing, especially under osteoporosis. However, precisely switching on and off inflammation around implants in vivo remains unachieved. To address this challenge, a "bridge-burning" coating material that comprises a macrophage-activating glycan covalently crosslinked by a macrophage-eliminating bisphosphonate to titanium implant surface is designed. Upon implantation, the glycan instructs host macrophages to release pro-osteogenic cytokines ("switch-on"), promoting bone cell differentiation. Later, increasingly mature bone cells secrete alkaline phosphatase to cleave the glycan-bisphosphonate complexes from the implant, which in turn selectively kill the proinflammatory macrophages ("switch-off") that have completed their contribution-hence in the manner of "burning bridges"-to promote healing. In vivo examination in an osteoporotic rat model demonstrates that this coating significantly enhances bone-implant integration (88.4% higher contact ratio) through modulating local inflammatory niches. In summary, a bioresponsive, endogenously triggered, smart coating material is developed to sequentially harness and abolish the power of inflammation to improve osseointegration under osteoporosis, which represents a new strategy for designing immunomodulatory biomaterials for tissue regeneration.

Advanced Functional MaterialsVolume 31, Issue 7 2170043 Inside Front CoverFree Access Osseointegration: Switching On and Off Macrophages by a "Bridge-Burning" Coating Improves Bone-Implant Integration under Osteoporosis (Adv. Funct. Mater. 7/2021) Zhenzhen Wang, Zhenzhen Wang State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, China State Key Laboratory of Pharmaceutical Biotechnology, Medical School & School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023 ChinaSearch for more papers by this authorYiming Niu, Yiming Niu State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, China State Key Laboratory of Pharmaceutical Biotechnology, Medical School & School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023 ChinaSearch for more papers by this authorXuejiao Tian, Xuejiao Tian State Key Laboratory of Pharmaceutical Biotechnology, Medical School & School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023 ChinaSearch for more papers by this authorNa Yu, Na Yu National Dental Centre Singapore, 5 Second Hospital Ave, Singapore, 168938 SingaporeSearch for more papers by this authorXiaoyu Yin, Xiaoyu Yin State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, ChinaSearch for more papers by this authorZhen Xing, Zhen Xing State Key Laboratory of Pharmaceutical Biotechnology, Medical School & School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023 ChinaSearch for more papers by this authorYurong Li, Yurong Li State Key Laboratory of Pharmaceutical Biotechnology, Medical School & School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023 ChinaSearch for more papers by this authorLei Dong, Lei Dong State Key Laboratory of Pharmaceutical Biotechnology, Medical School & School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023 China Chemistry and Biomedicine Innovative Center, Nanjing University, 163 Xianlin Avenue, Nanjing, 210093 ChinaSearch for more papers by this authorChunming Wang, Chunming Wang State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, ChinaSearch for more papers by this author Zhenzhen Wang, Zhenzhen Wang State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, China State Key Laboratory of Pharmaceutical Biotechnology, Medical School & School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023 ChinaSearch for more papers by this authorYiming Niu, Yiming Niu State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, China State Key Laboratory of Pharmaceutical Biotechnology, Medical School & School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023 ChinaSearch for more papers by this authorXuejiao Tian, Xuejiao Tian State Key Laboratory of Pharmaceutical Biotechnology, Medical School & School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023 ChinaSearch for more papers by this authorNa Yu, Na Yu National Dental Centre Singapore, 5 Second Hospital Ave, Singapore, 168938 SingaporeSearch for more papers by this authorXiaoyu Yin, Xiaoyu Yin State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, ChinaSearch for more papers by this authorZhen Xing, Zhen Xing State Key Laboratory of Pharmaceutical Biotechnology, Medical School & School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023 ChinaSearch for more papers by this authorYurong Li, Yurong Li State Key Laboratory of Pharmaceutical Biotechnology, Medical School & School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023 ChinaSearch for more papers by this authorLei Dong, Lei Dong State Key Laboratory of Pharmaceutical Biotechnology, Medical School & School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023 China Chemistry and Biomedicine Innovative Center, Nanjing University, 163 Xianlin Avenue, Nanjing, 210093 ChinaSearch for more papers by this authorChunming Wang, Chunming Wang State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, ChinaSearch for more papers by this author First published: 10 February 2021 https://doi.org/10.1002/adfm.202170043AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract In article number 2007408, Lei Dong, Chunming Wang, and co-workers invent a "bridge-burning" bioactive coating to sequentially turn on and off inflammation on bone implants. This coating first instructs host macrophages to activate bone cells to promote healing and then receives signals from bone cells to kill macrophages for higher safety. It improves bone-implant integration in mice with osteoporosis. Volume31, Issue7February 10, 20212170043 RelatedInformation

The discovery of protein corona (PC) formed on the surface of nanomaterials has promoted research on PC regulation to guide the biological behavior of nanomaterials in vivo. Different from changing the size, shape, and surface charge of nanoparticles, we propose to control the nature of PC by adjusting the molecular weight of low molecular weight polyethylene glycol (LMW PEG, not more than 1000 Da) on the surface of the particles. After excluding the influence of physicochemical factors of PEGylated gold nanoparticles (GNPs), different proteins on the surface of PEGylated GNPs were separated and identified after incubation with human plasma. It is noted that GNP-550 bearing PEG chains of 550 Da absorbed more transferrin responsible for tumor targeting than the other two particles, i.e., GNP-350 and GNP-1000. To validate our speculation, doxorubicin (Dox) was inserted between GNPs and PEGs to explore the cellular and animal studies of Dox-conjugated GNPs. Interestingly, Dox-containing Conj-550 also showed the highest intracellular uptake, cytotoxicity, and apoptosis against HepG2 cells, as well as the best tumor targeting effect and antitumor efficacy in Heps-bearing mice. This protein corona-guided tumor targeting therapy by transferrin provides a new perspective on the function modulation of nanomedicine via LMW PEGs.

Although chemotherapy and photothermal therapy are widely used to combat cancer, their efficacy is often limited by multidrug resistance. Small interfering RNAs (siRNAs) have ability to suppress the expression of target genes, which has been extensively employed for combating the multidrug resistance to chemodrugs and hyperthermia in cancer therapy. However, efficient delivery of siRNAs along with chemo-photothermal agents in vivo is still an enormous challenge. Herein, octahedral DNA origami frameworks (OctDOFs) are constructed as a nanovehicle for precise organization and orchestrated delivery of siRNAs, chemodrugs (doxorubicin, Dox), and photothermal agents (gold nanorods, AuNRs) in combinatorial treatment of cancer. The inner cavity of the rigid OctDOFs structure is able to shield the encapsulated siRNAs during transportation by sterically hindering RNase degradation and protein binding, thus achieving effective downregulation of connective tissue growth factor (CTGF) and heat shock protein 72 (HSP72) for dual sensitization of cancer cells to chemodrugs and hyperthermia. By amplifying chemo-photothermal therapeutic potency with siRNAs, the proposed OctDOFs exhibited superior cytotoxicity and tumor inhibition efficacy in vitro and in vivo. This nanovehicle creates a promising siRNA delivery platform for precise medication and combination therapy.

Administration of probiotics to regulate the immune system is a potential anti-tumor strategy. However, oral administration of probiotics is ineffective because of the poor inhabitation of exogenous bacteria in host intestines. Here we report that smectite, a type of mineral clay and established anti-diarrhea drug, promotes expansion of probiotics (especially Lactobacillus) in the murine gut and subsequently elicits anti-tumor immune responses. The ion-exchangeable microstructure of smectite preferentially promotes lactic acid bacteria (LABs) to form biofilms on smectite in vitro and in vivo. In mouse models, smectite laden with LAB biofilms (Lactobacillus and Bifidobacterium) inhibits tumor growth (when used alone) and enhances the efficacy of chemotherapy or immunotherapy (when used in combination with either of them) by activating dendritic cells (DCs) via Toll-like receptor 2 (TLR2) signaling. Our findings suggest oral administration of smectite as a promising strategy to enrich probiotics in vivo for cancer immunotherapy.