4.7 Article

pH-Responsive Dynaplexes as Potent Apoptosis Inductors by Intracellular Delivery of Survivin siRNA

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BIOMACROMOLECULES
卷 24, 期 8, 页码 3742-3754

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AMER CHEMICAL SOC
DOI: 10.1021/acs.biomac.3c00424

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Gene knockdown by siRNA is limited by the negative charge, large size, and susceptibility to enzymatic degradation of siRNA. In this study, a protein-based biodynamic polymer (biodynamer) was developed as a siRNA transfection vector, showing excellent biocompatibility, easy tunability, and dynamic polymerization under acidic conditions. The optimized biodynamers formed stable nanocomplexes with siRNA, exhibited pH-dependent size change and degradability, and effectively delivered siRNA into cells, resulting in potent gene knockdown and apoptosis of carcinoma cells. These findings suggest that the biodynamers hold immense potential as a promising platform for siRNA delivery.
Gene knockdown bysiRNA offers an unrestricted choice of targetsand specificity based on the principle of complementary Watson-Crickbase pairing with mRNA. However, the negative charge, large molecularsize, and susceptibility to enzymatic degradation of siRNA impedeits successful transfection, hence limiting its potential for therapeuticuse. The development of efficient and safe siRNA transfection agentsis, therefore, critical for siRNA-based therapy. Herein, we developeda protein-based biodynamic polymer (biodynamer) that showed potentialas a siRNA transfection vector, owing to its excellent biocompatibility,easy tunability, and dynamic polymerization under acidic environments.The positively charged biodynamers formed stable dynamic nanocomplexes(XL-DPs, hydrodynamic diameter of approximately 104 nm) with siRNAvia electrostatic interactions and chemical cross-linking. As a proofof concept, the optimized XL-DPs were stable in physiological conditionswith serum proteins and demonstrated significant pH-dependent sizechange and degradability, as well as siRNA release capability. Theminimal cytotoxicity and excellent cellular uptake of XL-DPs effectivelysupported the intracellular delivery of siRNA. Our study demonstratedthat the XL-DPs in survivin siRNA delivery enabled potent knockdownof survivin mRNA and induced notable apoptosis of carcinoma cells(2.2 times higher than a lipid-based transfection agent, Lipofectamine2000). These findings suggested that our XL-DPs hold immense potentialas a promising platform for siRNA delivery and can be considered strongcandidates in the advancement of next-generation transfection agents.

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