Metabolic skeletal disorders associated with impaired bone formation are a major clinical challenge. One approach to treat these defects is to silence bone-formation–inhibitory genes by small interference RNAs (siRNAs) in osteogenic-lineage cells that occupy the niche surrounding the bone-formation surfaces. We developed a targeting system involving dioleoyl trimethylammonium propane (DOTAP)-based cationic liposomes attached to six repetitive sequences of aspartate, serine, serine ((AspSerSer)6) for delivering siRNAs specifically to bone-formation surfaces. Using this system, we encapsulated an osteogenic siRNA that targets casein kinase-2 interacting protein-1 (encoded by Plekho1, also known as Plekho1). In vivo systemic delivery of Plekho1 siRNA in rats using our system resulted in the selective enrichment of the siRNAs in osteogenic cells and the subsequent depletion of Plekho1. A bioimaging analysis further showed that this approach markedly promoted bone formation, enhanced the bone micro-architecture and increased the bone mass in both healthy and osteoporotic rats. These results indicate (AspSerSer)6-liposome as a promising targeted delivery system for RNA interference–based bone anabolic therapy.
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We thank X.-H. Yang for technical support with the confocal imaging, H. Yang for technical support with the flow cytometry and F.C. Chun-Wan for assistance with the bone histomorphometry. This study was supported by the Chinese National Basic Research Programs (2011CB910602), the Hong Kong Competitive Earmarked Research Grant (CUHK479111 and 473011), the Direct Grant of Faculty of Medicine of the Chinese University of Hong Kong (2041478 and 2041525), the Faculty Research Grant of Hong Kong Baptist University (30-08-089), the Chinese National Natural Science Foundation Project (30830029) and the National Key Technologies Research and Development Program for New Drugs (2009ZX09503-002).
The authors declare no competing financial interests.
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Zhang, G., Guo, B., Wu, H. et al. A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy. Nat Med 18, 307–314 (2012). https://doi.org/10.1038/nm.2617
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