中文摘要：

將信使核糖核酸（mRNA）經(jīng)全身遞送至肝臟、脾臟、肺部以外的臟器，目前仍存在較大技術(shù)難題。為攻克該瓶頸，本研究提出假設(shè)：調(diào)整納米顆粒化學(xué)組分與給藥途徑，或可實(shí)現(xiàn)網(wǎng)狀內(nèi)皮系統(tǒng)以外臟器的 mRNA 靶向蛋白表達(dá)。本文報(bào)道一種利用脂質(zhì)納米顆粒高效、特異性靶向胰腺遞送 mRNA 的技術(shù)方案。實(shí)驗(yàn)結(jié)果證實(shí)，腹腔注射搭載陽(yáng)離子輔助脂質(zhì)的脂質(zhì)納米顆粒，能夠在胰腺組織中實(shí)現(xiàn)強(qiáng)效且特異的目標(biāo)蛋白表達(dá)，且蛋白主要在分泌胰島素的 β 細(xì)胞內(nèi)生成。研究進(jìn)一步證實(shí)，胰腺組織的 mRNA 遞送效應(yīng)依賴腹腔巨噬細(xì)胞分泌外泌體介導(dǎo)的水平基因轉(zhuǎn)移；該調(diào)控 mRNA 脂質(zhì)納米顆粒遞送效率的機(jī)制此前尚未得到充分關(guān)注。本遞送策略有望為糖尿病、胰腺癌等難治性胰腺疾病的基因治療提供全新技術(shù)支撐。

英文摘要：

Systemic messenger RNA (mRNA) delivery to organs outside the liver, spleen, and lungs remains challenging. To overcome this issue, we hypothesized that altering nanoparticle chemistry and administration routes may enable mRNA-induced protein expression outside of the reticuloendothelial system. Here, we describe a strategy for delivering mRNA potently and specifically to the pancreas using lipid nanoparticles. Our results show that delivering lipid nanoparticles containing cationic helper lipids by intraperitoneal administration produces robust and specific protein expression in the pancreas. Most resultant protein expression occurred within insulin-producing β cells. Last, we found that pancreatic mRNA delivery was dependent on horizontal gene transfer by peritoneal macrophage exosome secretion, an underappreciated mechanism that influences the delivery of mRNA lipid nanoparticles. We anticipate that this strategy will enable gene therapies for intractable pancreatic diseases such as diabetes and cancer.

論文信息：

論文題目：Ionizable lipid nanoparticles deliver mRNA to pancreatic β cells via macrophage-mediated gene transfer

期刊名稱：Science Advances

時(shí)間期卷：Vol 9, Issue4(2023)

在線時(shí)間：2023年1月27日

DOI: 10.1126/sciadv.ade1444

產(chǎn)品信息：

貨號(hào)：CP-005-005

規(guī)格：5ml+5ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes&Control Liposomes

辦事處：靶點(diǎn)科技

Clodronate Liposomes氯膦酸鹽脂質(zhì)體腹腔注射清除巨噬細(xì)胞后，特異性靶向胰腺遞送 mRNA脂質(zhì)納米顆粒遞送。荷蘭Liposoma巨噬細(xì)胞清除劑ClodronateLiposomes見(jiàn)刊于Science Advances：可電離脂質(zhì)納米顆粒通過(guò)巨噬細(xì)胞介導(dǎo)的基因遞送途徑，將信使核糖核酸遞送至胰腺 β 細(xì)胞。

Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes氯膦酸二鈉脂質(zhì)體清除巨噬細(xì)胞的材料和方法：

Macrophage depletion

All animal experiments were conducted using institutionally approved protocols (Institutional Animal Care and Use Committee). C57BL/6 mice (female unless otherwise indicated) were obtained from Charles River Laboratories, Wilmington, MA. STZ mice (males) and NOD and NOD/SCID mice (females) were obtained from the Jackson Laboratory (Bar Harbor, ME). STZ mice exhibited hyperglycemia (blood glucose > 250 mg/dl) upon arrival. In experiments involving clodronate liposomes, clodronate liposomes and control liposomes were purchased from Liposoma (Amsterdam, The Netherlands). Mice received intraperitoneal injections of 200 μl of clodronate or control liposomes 48 hours before LNP treatment. For fluorescence and luminescence studies, dissected organs were imaged using an IVIS (Perkin Elmer). In experiments using mRNA encoding luciferase, mice received an intraperitoneal injection of 130 μl of d-luciferin (30 mg/ml) 15 min before imaging. Blood samples were drawn via submandibular bleed and collected in Microtainer Serum Separator tubes (Becton Dickinson, Franklin Lakes, NJ).

巨噬細(xì)胞清除材料和方法文獻(xiàn)截圖：