Nayak Tapas R, Chrastina Adrian, Valencia Jose, Cordova-Robles Oscar, Yedidsion Robert, Buss Tim, Cederstrom Brittany, Koziol Jim, Levin Michael D, Olenyuk Bogdan, Schnitzer Jan E
Proteogenomics Research Institute for Systems Medicine, La Jolla, CA, USA.
Department of Chemistry, University of Utah, Salt Lake City, UT, USA.
Nat Nanotechnol. 2025 Jan;20(1):144-155. doi: 10.1038/s41565-024-01786-z. Epub 2024 Oct 8.
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.
现代医学追求精准靶向、成像和治疗，以实现疗效最大化并避免毒性。纳米颗粒（NPs）在全身携带和递送成像及治疗药物并实现组织精准性方面具有巨大但尚未满足的临床潜力。但其尺寸导致其被网状内皮系统快速清除，且难以穿透关键的内皮细胞（EC）屏障，从而限制了靶组织摄取、安全性和疗效。在此，我们发现内皮细胞小窝泵系统能够超越清除作用，将纳米颗粒快速且特异性地递送至肺部。金纳米颗粒和树枝状纳米颗粒与靶向肺微血管内皮细胞小窝的抗体偶联。单光子发射计算机断层扫描-计算机断层扫描（SPECT-CT）成像和生物分布分析显示，大鼠肺部在数分钟内摄取了大部分静脉注射剂量，从而实现了精准的肺部成像和靶向，肺部高浓度超过血药峰值水平。这些结果揭示了内皮细胞在多大程度上既能限制又能促进纳米颗粒的组织穿透，以及小窝泵系统的能力和尺寸依赖性限制。本研究为纳米颗粒提供了一种新的重新靶向范例，以避免网状内皮系统摄取，并实现快速精准的纳米递送，用于未来的诊断和治疗应用。
