title: Inter-molecular β-sheet structure facilitates lung-targeting siRNA delivery.
abstract: Size-dependent passive targeting based on the characteristics of tissues is a basic mechanism of drug delivery. While the nanometer-sized particles are efficiently captured by the liver and spleen, the micron-sized particles are most likely entrapped within the lung owing to its unique capillary structure and physiological features. To exploit this property in lung-targeting siRNA delivery, we designed and studied a multi-domain peptide named K-β, which was able to form inter-molecular β-sheet structures. Results showed that K-β peptides and siRNAs formed stable complex particles of 60 nm when mixed together. A critical property of such particles was that, after being intravenously injected into mice, they further associated into loose and micron-sized aggregates, and thus effectively entrapped within the capillaries of the lung, leading to a passive accumulation and gene-silencing. The large size aggregates can dissociate or break down by the shear stress generated by blood flow, alleviating the pulmonary embolism. Besides the lung, siRNA enrichment and targeted gene silencing were also observed in the liver. This drug delivery strategy, together with the low toxicity, biodegradability, and programmability of peptide carriers, show great potentials in vivo applications.
authors.affiliation: Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Jihan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wen
authors.affiliation: Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Shuquan
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Su
authors.affiliation: Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yi
authors.affiliation: Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.affiliation: Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Zicai
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Obstetrics &Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Tang
authors.affiliation: Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Demin
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Li-He
authors.initials: LH
authors.lastname: Zhang
authors.affiliation: Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Dehai
authors.initials: D
authors.lastname: Liang
authors.affiliation: Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Du
mesh_terms: D000818:Animals; D001688:Biological Products / Q000493:pharmacokinetics* / Q000633:toxicity; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000493:pharmacokinetics* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D011487:Protein Conformation; D000072757:Protein Conformation, beta-Strand; D055503:Protein Multimerization; D034741:RNA, Small Interfering / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D001688:Biological Products; D002352:Carrier Proteins; D004337:Drug Carriers; D034741:RNA, Small Interfering