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1. Exosome-Liposome Hybrid Nanoparticles Deliver CRISPR/Cas9 System in MSCs

? Targeted delivery of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system to the receptor cells is essential for in vivo gene editing. Exosomes are intensively studied as a promising targeted drug delivery carrier recently, while limited by their low efficiency in encapsulating of large nucleic acids. Here, a kind of hybrid exosomes with liposomes is developed via simple incubation. Different from the original exosomes, the resultant hybrid nanoparticles efficiently encapsulate large plasmids, including the CRISPR-Cas9 expression vectors, similarly as the liposomes. Moreover, the resultant hybrid nanoparticles can be endocytosed by and express the encapsulated genes in the mesenchymal stem cells (MSCs), which cannot be transfected by the liposome alone. Taken together, the exosome-liposome hybrid nanoparticles can deliver CRISPR-Cas9 system in MSCs and thus be promising in in vivo gene manipulation.

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Advanced Science (Adv Sci (Weinh). 2018 Jan 30;5(4):1700611.

Exosome-Liposome Hybrid Nanoparticles Deliver CRISPR/Cas9 System in MSCs

Yao Lin, Jiahua Wu, Weihuai Gu, Yulei Huang, Zhongchun Tong, Lijia Huang, and Jiali Tan

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2. Sustained Release of Two Bioactive Factors from Supramolecular Hydrogel Promotes Periodontal Bone Regeneration

? Intact and stable bone reconstruction is ideal for the treatment of periodontal bone destruction but remains challenging. In research, biomaterials are used to encapsulate stem cells or bioactive factors for periodontal bone regeneration, but, to the best of our knowledge, using a supramolecular hydrogel to encapsulate bioactive factors for their sustained release in bone defect areas to promote periodontal bone regeneration has not been reported. Herein, we used a well-studied hydrogelator, NapFFY, to coassemble with SDF-1 and BMP-2 to prepare a supramolecular hydrogel, SDF-1/BMP-2/NapFFY. In vitro and in vivo results indicated that these two bioactive factors were ideally, synchronously, and continuously released from the hydrogel to effectively promote the regeneration and reconstruction of periodontal bone tissues. Specifically, after the bone defect areas were treated with our SDF-1/BMP-2/NapFFY hydrogel for 8 weeks using maxillary critical-sized periodontal bone defect model rats, a superior bone regeneration rate of 56.7% bone volume fraction was achieved in these rats. We anticipate that our SDF-1/BMP-2/NapFFY hydrogel could replace bone transplantation in the clinic for the repair of periodontal bone defects and periodontally accelerated osteogenic orthodontics in the near future.

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ACS Nano.?2019 May 28;13(5):5616-5622.

Sustained Release of Two Bioactive Factors from Supramolecular Hydrogel Promotes Periodontal Bone Regeneration

Jiali Tan, Mei Zhang, Zijuan Hai, Chengfan Wu , Jiong Lin, Wen Kuang, Hang Tang, Yulei Huang , Xiaodan Chen , Gaolin Liang

3. Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity

? Purpose: Multiple negative regulators restrict the ability of T cells to attack tumors. This work demonstrates the role of PI3K-interacting protein 1 (Pik3ip1) in restraining T-cell responses and antitumor immunity.

Experimental design: An anti-Pik3ip1 mAb was generated to identify the Pik3ip1 expression pattern of hematopoietic cells. Pik3ip1 -/- mice and a Pik3ip1 fusion protein were generated to investigate the effect of Pik3ip1 on T-cell-mediated antitumor immunity in MC38 and B16-F10 tumor models. Immunoblotting and confocal microscopy were used to identify inhibitory effects of Pik3ip1 on T-cell receptor (TCR) signaling. Pik3ip1 expression was quantified, and its impact on T-cell function in human tumors was measured.

Results: We demonstrated that Pik3ip1 was predominantly expressed on T cells and served as an essential rheostat for T-cell-mediated immunity. A Pik3ip1 genetic deficiency led to enhanced T-cell responsiveness upon immunization with a neoantigen. Pik3ip1 -/- mice exhibited a marked increase in antitumor immunity and were resistant to tumor growth. Furthermore, Pik3ip1 extracellular domain fusion protein enhanced MC38 tumor growth was observed. Mechanistically, we found that Pik3ip1 inhibited TCR signaling by mediating the degradation of SLP76 through Pik3ip1 oligomerization via its extracellular region. Consistent with the results from the mouse models, PIK3IP1 expression correlated with T-cell dysfunction in human tumors.

Conclusions: Our data reveal a critical role for Pik3ip1 as a novel inhibitory immune regulator of T-cell responses and provide a potential molecular target for cancer immunotherapy.

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Clin Cancer Res. 2019 Oct 15;25(20):6180-6194.

Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity

Yichen Chen , Jun Wang , Xi Wang , Xinye Li , Jingjing Song , Juan Fang , Xiangqi Liu , Tao Liu , Dikan Wang, Qunxing Li , Shuqiong Wen , Da Ma , Juan Xia, Liqun Luo, Song Guo Zheng , Jun Cui , Gucheng Zeng , Lieping Chen , Bin Cheng , Zhi Wang.

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4. Calnexin Impairs the Antitumor Immunity of CD4 + and CD8 + T Cells

? Elucidation of the mechanisms of T-cell-mediated antitumor responses will provide information for the rational design and development of cancer immunotherapies. Here, we found that calnexin, an endoplasmic reticulum (ER) chaperone protein, is significantly upregulated in oral squamous cell carcinoma (OSCC). Upregulation of its membranous expression on OSCC cells is associated with inhibited T-cell infiltration in tumor tissues and correlates with poor survival of patients with OSCC. We found that calnexin inhibits the proliferation of CD4+ and CD8+ T cells isolated from the whole blood of healthy donors and patients with OSCC and inhibits the secretion of IFN¦Ã, TNF¦Á, and IL2 from these cells. Furthermore, in a melanoma model, knockdown of calnexin enhanced the infiltration and effector functions of T cells in the tumor microenvironment and conferred better control of tumor growth, whereas treatment with a recombinant calnexin protein impaired the infiltration and effector functions of T cells and promoted tumor growth. We also found that calnexin enhanced the expression of PD-1 on CD4+ and CD8+ T cells by restraining the DNA methylation status of a CpG island in the PD-1 promoter. Thus, this work uncovers a mechanism by which T-cell antitumor responses are regulated by calnexin in tumor cells and suggests that calnexin might serve as a potential target for the improvement of antitumor immunotherapy.

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Cancer Immunol Res. 2019 Jan;7(1):123-135.

Calnexin Impairs the Antitumor Immunity of CD4 + and CD8 + T Cells

Yichen Chen , Da Ma , Xi Wang , Juan Fang , Xiangqi Liu , Jingjing Song , Xinye Li , Xianyue Ren , Qiusheng Li , Qunxing Li , Shuqiong Wen , Liqun Luo , Juan Xia, Jun Cui , Gucheng Zeng , Lieping Chen , Bin Cheng , Zhi Wang