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Efficient and targeted drug/siRNA co-delivery mediated by reversibly crosslinked polymersomes toward anti-inflammatory treatment of ulcerative colitis (UC)

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Abstract

Co-delivery of anti-inflammatory siRNA and hydrophilic drug provides a promising approach for the treatment of ulcerative colitis (UC). However, lack of a suitable and efficient co-delivery carrier poses critical challenge against their utilization. We herein developed macrophage-targeting, reversibly crosslinked polymersomes (TKPR-RCP) based on the TKPR-modified, poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) triblock copolymer, which could efficiently encapsulate TNF-α siRNA and dexamethasone sodium phosphate (DSP) in their hydrophilic core. The cationic PEI segments provided additional electrostatic interactions with cargo molecules to promote the encapsulation, and disulfide crosslinking of the polymersome membrane endowed the TKPR-RCP with high colloidal stability. Because the cationic PEI was embedded in the hydrophilic core, the polymersomes displayed neutral surface charge and thus possessed high serum stability. The TKPR-RCP co-encapsulating TNF-α siRNA and DSP could be efficiently internalized by macrophages (∼ 98%) and undergo redox-responsive membrane de-crosslinking to accelerate cargo release in the cytoplasm, thus inducing efficient gene silencing and anti-inflammatory effect. Intravenous injection of the co-delivery TKPR-RCP mediated potent and cooperative anti-inflammatory effect in inflamed colons of UC mice, and significantly prevented animals from colonic injury. This study therefore provides a promising approach for the co-delivery of hydrophilic drug/siRNA toward the treatment of inflammatory bowel diseases.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Nos. 51573123, 51722305, and 51633005), the Ministry of Science and Technology of China (No. 2016YFA0201200), 111 project, and Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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  1. Xin Xu and Weijing Yang contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Institute of Functional Nano and Soft Materials (FUNSOM), the Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, 215123, China

    Xin Xu, Qiujun Liang, Wenxin Zhang, Xiao Wang & Lichen Yin

  2. Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, China

    Weijing Yang, Yanan Shi, Fenghua Meng & Zhiyuan Zhong

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  1. Xin Xu
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Correspondence to Zhiyuan Zhong or Lichen Yin.

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12274_2019_2274_MOESM1_ESM.pdf

Efficient and targeted drug/siRNA co-delivery mediated by reversibly crosslinked polymersomes toward anti-inflammatory treatment of ulcerative colitis (UC)

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Xu, X., Yang, W., Liang, Q. et al. Efficient and targeted drug/siRNA co-delivery mediated by reversibly crosslinked polymersomes toward anti-inflammatory treatment of ulcerative colitis (UC). Nano Res. 12, 659–667 (2019). https://doi.org/10.1007/s12274-019-2274-2

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