为了实现磁共振成像（MRI）对肿瘤的准确诊断，近年来研发了基于极小铁氧化物纳米颗粒（ESIONPs）的可切换T1和T2对比度增强的磁共振对比剂（CAs）。我们首次报道了一种基于ESIONP的新型纳米团簇（命名为EAmP），该团簇对肿瘤微环境呈现缺氧响应，并提供了T2到T1可切换的对比度增强功能，有效区分正常组织和肿瘤组织。具体来说，首先合成了直径约为3.6纳米的活性全氟苯酯修饰的ESIONP，然后利用4,4'-偶氮苯胺作为交联剂，通过活性酯与胺之间的反应促进ESIONP形成纳米团簇。最后，利用剩余的活性酯残基对纳米团簇进行聚乙二醇修饰。得到的EAmP表现出良好的胶体稳定性和良好的生物安全性，并在溶液中模拟缺氧环境下，从纳米团簇向分散状态转化，并且r2/r1比值从14.86降至1.61。此外，EAmP能够在肿瘤区域分解为分散的ESIONPs，从而实现T2到T1对比度增强的切换。这种T2到T1可切换的对比剂具有高灵敏度和信噪比，可实现肿瘤的准确诊断。总之，缺氧响应性EAmP是一种潜在的改善实体肿瘤诊断准确性的MRI纳米探针。

To realize the accurate diagnosis of tumors by magnetic resonance imaging (MRI), switchable magnetic resonance contrast agents (CAs) between T1 and T2 contrast enhancement that are constructed based on extremely small iron oxide nanoparticles (ESIONPs) have been developed in recent years. We herein report, for the first time, a novel ESIONP-based nanocluster (named EAmP), which exhibited hypoxia responsiveness to the tumor microenvironment and offered a T2-to-T1-switchable contrast enhancement function, effectively distinguishing between the normal tissue and tumor tissue. In detail, active perfluorophenyl ester-modified ESIONPs with a diameter of approximately 3.6 nm were initially synthesized, and then 4,4'-azodianiline was used as a cross-linker to facilitate the formation of nanoclusters from ESIONPs through the reaction between the active ester and amine. Finally, poly(ethylene glycol) was further modified onto nanoclusters by utilizing the remaining active ester residues. The resulting EAmP demonstrated satisfactory colloidal stability and favorable biosafety and exhibited a desired T2-to-T1-switchable function, as evidenced by conversion from nanocluster to the dispersed state and a significant decrease in the r2/r1 ratio from 14.86 to 1.61 when exposed to a mimical hypoxic environment in the solution. Moreover, EAmP could decompose into dispersed ESIONPs at the tumor region, resulting in a switch from T2 to T1 contrast enhancement. This T2-to-T1-switchable contrast agent offers high sensitivity and signal-to-noise ratio to realize the accurate diagnosis of tumors. In conclusion, hypoxia-responsive EAmP is a potential MRI nanoprobe for improving the diagnostic accuracy of solid tumors.