A major critical issue in systemically administered nanomedicines is nonspecific clearance by the liver sinusoidal endothelium, causing a substantial decrease in the delivery efficiency of nanomedicines into the target tissues. Here, we addressed this issue by in situ stealth coating of liver sinusoids using linear or two-armed poly(ethylene glycol) (PEG)–conjugated oligo(l-lysine) (OligoLys). PEG-OligoLys selectively attached to liver sinusoids for PEG coating, leaving the endothelium of other tissues uncoated and, thus, accessible to the nanomedicines. Furthermore, OligoLys having a two-armed PEG configuration was ultimately cleared from sinusoidal walls to the bile, while OligoLys with linear PEG persisted in the sinusoidal walls, possibly causing prolonged disturbance of liver physiological functions. Such transient and selective stealth coating of liver sinusoids by two-arm-PEG-OligoLys was effective in preventing the sinusoidal clearance of nonviral and viral gene vectors, representatives of synthetic and nature-derived nanomedicines, respectively, thereby boosting their gene transfection efficiency in the target tissues.

全身给药纳米药物的一个主要关键问题是肝窦内皮的非特异性清除，导致纳米药物进入靶组织的递送效率显着降低。在这里，我们通过使用线性或双臂聚（乙二醇）（PEG）共轭寡核苷酸（l-赖氨酸）（寡核苷酸）。PEG-OligoLys 选择性地附着在肝血窦上进行 PEG 涂层，使其他组织的内皮未被涂层，因此纳米药物可以使用。此外，具有双臂 PEG 构型的 OligoLys 最终从肝窦壁清除至胆汁，而具有线性 PEG 的 OligoLys 则持续存在于肝窦壁中，可能导致肝脏生理功能的长期紊乱。双臂 PEG-OligoLys 对肝窦的这种瞬时和选择性隐形涂层可有效防止非病毒和病毒基因载体的肝窦清除，分别代表合成和天然衍生的纳米药物，从而提高其基因转染效率目标组织。