One of the goals of nanomedicine is targeted delivery of therapeutic enzymes to the sub-cellular compartments where their action is needed. Endothelial caveolae-derived endosomes represent an important yet challenging destination for targeting, in part due to smaller size of the entry aperture of caveolae (ca. 30–50 nm). Here, we designed modular, multi-molecular, ferritin-based nanocarriers with uniform size (20 nm diameter) for easy drug-loading and targeted delivery of enzymatic cargo to these specific vesicles. These nanocarriers targeted to caveolar Plasmalemmal Vesicle-Associated Protein (Plvap) deliver superoxide dismutase (SOD) into endosomes in endothelial cells, the specific site of influx of superoxide mediating by such pro-inflammatory signaling as some cytokines and lipopolysaccharide (LPS). Cell studies showed efficient internalization of Plvap-targeted SOD-loaded nanocarriers followed by dissociation from caveolin-containing vesicles and intracellular transport to endosomes. The nanocarriers had a profound protective anti-inflammatory effect in an animal model of LPS-induced inflammation, in agreement with the characteristics of their endothelial uptake and intracellular transport, indicating that these novel, targeted nanocarriers provide an advantageous platform for caveolae-dependent delivery of biotherapeutics.

纳米医学的目标之一是将治疗酶靶向递送至需要其作用的亚细胞区室。内皮细胞小窝衍生的内体代表了一个重要但具有挑战性的靶向目的地，部分原因是小窝的入口孔径较小（约 30-50 nm）。在这里，我们设计了尺寸均匀（直径 20 nm）的模块化、多分子、基于铁蛋白的纳米载体，以便轻松装载药物并将酶货物靶向递送到这些特定的囊泡。这些靶向小穴质膜囊泡相关蛋白 (Plvap) 的纳米载体将超氧化物歧化酶 (SOD) 递送至内皮细胞的内体中，内皮细胞是超氧化物流入的特定位点，由一些细胞因子和脂多糖 (LPS) 等促炎信号传导介导。细胞研究表明，Plvap 靶向的 SOD 负载纳米载体可有效内化，然后从含有小窝蛋白的囊泡中解离，并在细胞内转运至内体。纳米载体在脂多糖诱导的炎症动物模型中具有深远的保护性抗炎作用，与其内皮摄取和细胞内运输的特征一致，表明这些新颖的靶向纳米载体为小凹依赖性递送提供了有利的平台。生物治疗学。