Modern medicine seeks precision targeting, imaging and therapy to maximize efficacy and avoid toxicities. Nanoparticles (NPs) have tremendous yet unmet clinical potential to carry and deliver imaging and therapeutic agents systemically with tissue precision. But their size contributes to rapid scavenging by the reticuloendothelial system and poor penetration of key endothelial cell (EC) barriers, limiting target tissue uptake, safety and efficacy. Here we discover the ability of the EC caveolae pumping system to outpace scavenging and deliver NPs rapidly and specifically into the lungs. Gold and dendritic NPs are conjugated to antibodies targeting caveolae of the lung microvascular endothelium. SPECT-CT imaging and biodistribution analyses reveal that rat lungs extract most of the intravenous dose within minutes to achieve precision lung imaging and targeting with high lung concentrations exceeding peak blood levels. These results reveal how much ECs can both limit and promote tissue penetration of NPs and the power and size-dependent limitations of the caveolae pumping system. This study provides a new retargeting paradigm for NPs to avoid reticuloendothelial system uptake and achieve rapid precision nanodelivery for future diagnostic and therapeutic applications.

现代医学寻求精确靶向、成像和治疗，以最大限度地提高疗效并避免毒性。纳米颗粒 （NPs） 具有巨大但尚未得到满足的临床潜力，可以系统地以组织精度携带和输送成像和治疗剂。但它们的大小有助于网状内皮系统的快速清除和关键内皮细胞 （EC） 屏障的渗透不良，从而限制了靶组织的摄取、安全性和有效性。在这里，我们发现了 EC 小窝泵送系统的能力，它能够超越清除速度，并将 NP 快速、特异性地输送到肺部。金和树突状 NP 与靶向肺微血管内皮小窝的抗体偶联。SPECT-CT 成像和生物分布分析显示，大鼠肺在几分钟内提取大部分静脉剂量，以实现精确的肺部成像和靶向，肺浓度超过血液峰值水平。这些结果揭示了 EC 的数量可以限制和促进 NP 的组织渗透，以及小窝泵送系统的功率和大小依赖性限制。本研究为 NPs 提供了一种新的重定向范式，以避免网状内皮系统摄取，并为未来的诊断和治疗应用实现快速精准的纳米递送。