纳米医药已获批用于治疗多种人类疾病。然而，纳米制剂的临床采用常常受到肝脏摄取和清除的担忧的阻碍，这是一个尚未完全理解的过程。在这里，我们展示了癌症纳米医药的抗肿瘤疗效呈现出一种与年龄相关的差异。在老年和年轻小鼠中，肿瘤递送和治疗效果较好，这可能是由于肝脏噬菌细胞摄取和清除纳米颗粒的能力在老年人群中随着年龄的增长而下降。单细胞和批量水平的转录组和蛋白质水平分析显示，在小鼠、非人类灵长类动物和人类中，肝脏巨噬细胞中表达清道夫受体MARCO的细胞数量与年龄相关的减少。疗法性地阻断MARCO被证明可以降低纳米颗粒的吞噬摄取，并改善在年轻小鼠中但不是老年小鼠中临床批准的癌症纳米治疗剂的抗肿瘤效果。综上所述，这些结果揭示了与年龄相关的纳米治疗剂吞噬清除的差异对其抗肿瘤反应的影响，从而为癌症纳米医药的年龄适应性方法提供了有力的理论依据。© 2023. 作者授权给斯普林格自然有限公司独家使用许可。

Nanomedicines have been approved to treat multiple human diseases. However, clinical adoption of nanoformulated agents is often hindered by concerns about hepatic uptake and clearance, a process that is not fully understood. Here we show that the antitumour efficacy of cancer nanomedicine exhibits an age-associated disparity. Tumour delivery and treatment outcomes are superior in old versus young mice, probably due to an age-related decline in the ability of hepatic phagocytes to take up and remove nanoparticles. Transcriptomic- and protein-level analysis at the single-cell and bulk levels reveals an age-associated decrease in the numbers of hepatic macrophages that express the scavenger receptor MARCO in mice, non-human primates and humans. Therapeutic blockade of MARCO is shown to decrease the phagocytic uptake of nanoparticles and improve the antitumour effect of clinically approved cancer nanotherapeutics in young but not aged mice. Together, these results reveal an age-associated disparity in the phagocytic clearance of nanotherapeutics that affects their antitumour response, thus providing a strong rationale for an age-appropriate approach to cancer nanomedicine.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.