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The silencing of disease-causing genes with small interfering RNA (siRNA) offers a particularly effective therapeutic strategy for different disorders; however, its clinical efficacy relies on the development of nontoxic and tissue-specific delivery vehicles. Herein, we report that bioresponsive chimaeric polymersomes (BCP) with short poly(ethylenimine) as inner shell mediate highly efficacious, sustained, and liver-specific siRNAtransfection in vivo. BCP exhibited remarkable encapsulation efficiencies of siRNA(95–100%) at siRNA-feeding contents of 15–25 wt %, to afford stable, small-sized (55–64 nm), and neutral-charged BCP-siRNA. siApoB-Loaded BCP (BCP-siApoB) outperformed lipofectamine counterparts and silenced 93% of ApoBmRNA in HepG2 cells at 50 nM siApoBwithout inducing cytotoxicity. Intriguingly, the in vivostudies using wild-type C57BL/6 mice revealed that BCP-siApoBpreferentially accumulated in the liver, and a single dose of 4.5 mg/kg achieved over 90% downregulation of ApoBmRNA for at least 10 days. The systemic administration of BCP-siApoBat 4.5 mg/kg every 2 weeks or 1.5 mg/kg weekly in diet-induced obese mice could also achieve up to 80% silencing of ApoBmRNA. The liver specificity and silencing efficacy of BCP-siApoBcould further be improved by decorating it with the trivalent N-acetylgalactosamine (TriGalNAc) ligand. These bioresponsive and liver-specific chimaeric polymersomes provide an enabling technology for siRNAtherapy of various liver-related diseases.

Photosynthesis is the fundamental basis of plant growth and development, and the improvement of photosynthetic efficiency can therefore promote increased crop yields. In this study, a comparative analysis of photosynthetic physiology and transcriptome was conducted between the high photosynthetic efficient variety BN207 and its parents BN64 and ZM16. The higher chlorophyll fluorescence, chlorophyll and carotenoid contents, and Lhcb1 protein accumulation in BN207 improved photosynthetic efficiency by promoting light energy absorption and conversion. Chloroplasts being distributed more closely to the cell membrane and the higher Rubisco enzyme activity of BN207 enhanced carbon assimilation, resulting in more carbohydrate accumulation in BN207. Transcriptome analysis revealed that there were several key genes mediating the high photosynthetic efficiency of BN207: TraesCS5D02G364100 (chlorophyllase), BGI_novel_G006617 (lycopene ɛ-cyclase), TraesCS4A02G034800 and TraesCS4A02G035100 (Zeaxanthin epoxidase), TraesCS6B02G122500 (light-harvesting complex II chlorophyll a/bbinding protein 1). These genes improved the photosynthetic efficiency of BN207 mainly by reducing chlorophyll degradation, promoting carotenoid synthesis, and increasing Lhcb1 protein accumulation. These findings provide important background information for the cultivation of wheat varieties with high photosynthetic efficiency.

Triptolide has been intensively studied in numerous preclinical and clinical assessments for immunosuppressive and anti-tumor activities. However, further clinical use is limited by the cumulative toxicity of triptolide in the testis and the mechanisms are poorly understood. In this study, we found significant triptolide accumulation in the testis, and further investigated the role of efflux transporters in its accumulation and toxicity. Chronic administration of triptolide induced time- and dose-dependent testicular injury and resulted in the accumulation of triptolide in the liver and testis, but not in the plasma. Using transporter-expressed cells, triptolide efflux was found in BCRP-expressing cells, which could be blocked by novobiocin (an inhibitor of BCRP) in accumulation assays. Triptolide also displayed apically directed transport across BCRP-expressing cell layers in transwell assays, strongly supporting that triptolide is a substrate of BCRP. Bcrp knockout mice (Bcrp−/−) were further used to examine the effects of triptolide. Knockout of Bcrp aggravated triptolide-induced testicular injury and increased the testis content and testis to plasma ratio of triptolide in Bcrp−/−mice. Notably, triptolide decreased the transcript and protein levels of Bcrp in the testis, which may be due to the downregulation of RNA polymerase II. In conclusion, as a substrate of BCRP, triptolide decreased the expression of Bcrp and RNA polymerase II in the testis, and further increased the testis content and enhanced its testicular toxicity, which contributes to the cumulative toxicity of triptolide in the testis.