The development of effective oral drug delivery systems for targeted gut-to-liver transport remains a significant challenge due to the multiple biological barriers including the harsh gastrointestinal tract (GIT) environment and the complex protein corona (PC) formation. In this study, we developed ligand-modified nanoparticles (NPs) that enable gut-to-liver drug delivery by crossing the GIT and attenuating PC formation. Specifically, mesoporous silica nanoparticles (MSNs) were functionalized with peptides targeting the neonatal Fc receptor (FcRn), capitalizing on FcRn expression in the small intestine and liver for targeted drug delivery. We showed that MSNs decorated with a small cyclic FcRn binding peptide (MSNs-FcBP) obtained enhanced diffusion in intestinal mucus and superior transportation across the intestine compared to unmodified MSNs and MSNs decorated with a large IgG Fc fragment (MSNs-Fc), which correlated with diminished protein adsorption and weaker interaction with mucin. After entering the blood circulation, reduced serum PC formation by MSNs-FcBP reduces the proteolytic and phagocytic propensity of the reticuloendothelial system, ultimately ameliorating accumulation in hepatocytes. Pharmacokinetic and pharmacodynamic studies in diabetic mice revealed that MSNs-FcBP effectively transported the therapeutic agent exenatide across the intestinal epithelium, leading to a significant hypoglycemic response and improved glucose tolerance. This study underscores the critical role of ligand selection in limiting protein corona formation, thereby significantly enhancing gut-to-liver drug delivery by increasing mucus permeation and minimizing serum–protein interactions. The effective delivery of exenatide in diabetic mice illustrates the potential of this strategy to optimize oral drug bioavailability and therapeutic efficacy.

中文翻译：

---

通过减弱蛋白质电晕吸附，通过配体修饰的纳米颗粒增强肠到肝的口服药物递送


由于存在多种生物屏障，包括恶劣的胃肠道 （GIT） 环境和复杂的蛋白质电晕 （PC） 形成，开发用于靶向肠道到肝脏运输的有效口服药物递送系统仍然是一项重大挑战。在这项研究中，我们开发了配体修饰的纳米颗粒 （NPs），它通过穿过 GIT 和减弱 PC 形成来实现肠道到肝脏的药物递送。具体来说，介孔二氧化硅纳米颗粒 （MSN） 用靶向新生儿 Fc 受体 （FcRn） 的肽进行功能化，利用小肠和肝脏中的 FcRn 表达进行靶向药物递送。我们发现，与未修饰的 MSN 和用大 IgG Fc 片段 （MSN-Fc） 修饰的 MSN 相比，用小环状 FcRn 结合肽 （MSN-FcBP） 修饰的 MSN 在肠粘液中的扩散增强和在肠道中的转运优越，这与蛋白质吸附减少和与粘蛋白的相互作用较弱相关。进入血液循环后，MSN-FcBP 减少的血清 PC 形成降低了网状内皮系统的蛋白水解和吞噬倾向，最终改善了肝细胞中的积累。糖尿病小鼠的药代动力学和药效学研究表明，MSNs-FcBP 有效地将治疗剂艾塞那肽转运到肠上皮，导致显着的低血糖反应和葡萄糖耐量改善。本研究强调了配体选择在限制蛋白质电晕形成中的关键作用，从而通过增加粘液渗透和最大限度地减少血清-蛋白质相互作用来显着增强肠道到肝脏的药物递送。 艾塞那肽在糖尿病小鼠中的有效递送说明了这种策略在优化口服药物生物利用度和治疗效果方面的潜力。