PMID- 29629115 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200929 IS - 2041-6520 (Print) IS - 2041-6539 (Electronic) IS - 2041-6520 (Linking) VI - 9 IP - 2 DP - 2018 Jan 14 TI - H(2)O(2)-responsive and plaque-penetrating nanoplatform for mTOR gene silencing with robust anti-atherosclerosis efficacy. PG - 439-445 LID - 10.1039/c7sc03582a [doi] AB - The mammalian target of rapamycin (mTOR) that controls autophagy and lipid metabolism is pivotal for atherosclerosis initiation and progression. Although blocking the mTOR function with rapamycin and its analogs may stimulate autophagy and consequently attenuate lipid storage and atherosclerotic lesions, only limited success has been achieved in clinical applications due to the unsatisfactory efficacy and safety profiles. In this study, we engineered a cerium oxide nanowire (CeO(2) NW)-based RNA interference (RNAi) oligonucleotide delivery nanoplatform for the effective silencing of mTOR and treatment of atherosclerosis. This nanoplatform is composed of the following three key components: (i) a stabilin-2-specific peptide ligand (S2P) to improve plaque targeting and penetration; (ii) polyethylene glycosylation (PEGylation) to extend in vivo circulation time; and (iii) a high aspect ratio CeO(2) core to facilitate endosome escape and ensure "on-demand" release of the RNAi payloads through competitive coordination of cytosolic hydrogen peroxide (H(2)O(2)). Systemic administration of the nanoplatforms efficiently targeted stabilin-2-expressing plaque and suppressed mTOR expression, which significantly rescued the impaired autophagy and inhibited the atherosclerotic lesion progression in apolipoprotein E-deficient (ApoE(-)/(-)) mice fed with a high-fat diet. These results demonstrated that this H(2)O(2)-responsive and plaque-penetrating nanoplatform can be a potent and safe tool for gene therapy of atherosclerosis. FAU - Gao, Wen AU - Gao W AD - College of Chemistry, Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Biomedical Sciences , Shandong Normal University , Jinan 250014 , P. R. China . Email: tangb@sdnu.edu.cn. FAU - Zhao, Yujie AU - Zhao Y AD - College of Chemistry, Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Biomedical Sciences , Shandong Normal University , Jinan 250014 , P. R. China . Email: tangb@sdnu.edu.cn. FAU - Li, Xiang AU - Li X AD - College of Chemistry, Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Biomedical Sciences , Shandong Normal University , Jinan 250014 , P. R. China . Email: tangb@sdnu.edu.cn. FAU - Sun, Yuhui AU - Sun Y AD - College of Chemistry, Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Biomedical Sciences , Shandong Normal University , Jinan 250014 , P. R. China . Email: tangb@sdnu.edu.cn. FAU - Cai, Michelle AU - Cai M AD - Faculty of Science , Western University , London , Ontario N6A5B7 , Canada. FAU - Cao, Wenhua AU - Cao W AD - College of Chemistry, Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Biomedical Sciences , Shandong Normal University , Jinan 250014 , P. R. China . Email: tangb@sdnu.edu.cn. FAU - Liu, Zhenhua AU - Liu Z AD - College of Chemistry, Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Biomedical Sciences , Shandong Normal University , Jinan 250014 , P. R. China . Email: tangb@sdnu.edu.cn. FAU - Tong, Lili AU - Tong L AD - College of Chemistry, Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Biomedical Sciences , Shandong Normal University , Jinan 250014 , P. R. China . Email: tangb@sdnu.edu.cn. FAU - Cui, Guanwei AU - Cui G AD - College of Chemistry, Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Biomedical Sciences , Shandong Normal University , Jinan 250014 , P. R. China . Email: tangb@sdnu.edu.cn. FAU - Tang, Bo AU - Tang B AUID- ORCID: 0000-0002-8712-7025 AD - College of Chemistry, Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Biomedical Sciences , Shandong Normal University , Jinan 250014 , P. R. China . Email: tangb@sdnu.edu.cn. LA - eng PT - Journal Article DEP - 20171027 PL - England TA - Chem Sci JT - Chemical science JID - 101545951 PMC - PMC5868311 EDAT- 2018/04/10 06:00 MHDA- 2018/04/10 06:01 PMCR- 2017/10/27 CRDT- 2018/04/10 06:00 PHST- 2017/08/16 00:00 [received] PHST- 2017/10/27 00:00 [accepted] PHST- 2018/04/10 06:00 [entrez] PHST- 2018/04/10 06:00 [pubmed] PHST- 2018/04/10 06:01 [medline] PHST- 2017/10/27 00:00 [pmc-release] AID - c7sc03582a [pii] AID - 10.1039/c7sc03582a [doi] PST - epublish SO - Chem Sci. 2017 Oct 27;9(2):439-445. doi: 10.1039/c7sc03582a. eCollection 2018 Jan 14.