Nanomedicine is revolutionizing the treatment of cancer and has achieved unprecedented outcomes over the past decades. The accumulation of Nanoparticles (NPs) in different tumors relies mainly on the Enhanced Permeability and Retention (EPR) effect benefiting from the wide fenestrae of the tumor vasculature and the lack of lymphatic drainage. However, the EPR effect is recognized as a heterogeneous phenomenon resulting in heterogeneous outcomes of clinical trials. Extensive efforts are exerted to enhance the outcomes of nanomedicine in a larger cohort of patients by employing active targeting strategies. However, actively targeted NPs accumulate in tumors by the EPR effect and hence fail to achieve convincing therapeutic outcomes. These obstacles are gradually being removed by improving the understanding of the Tumor Microenvironment (TME) and the mechanistic interaction of the NPs with its different components. In this review, we provide detailed insights into the past concerns of drug targeting, the current trends of TME reengineering, and the future implications for overcoming past hurdles. Strategies explored in this regard included the use of companion diagnostics and the modulation of the protein corona associated with the systemic administration of NPs and their interaction with biological macromolecules.

纳米医学正在彻底改变癌症的治疗方法，并在过去几十年中取得了前所未有的成果。纳米颗粒 (NPs) 在不同肿瘤中的积累主要依赖于增强的渗透性和保留 (EPR) 效应，受益于肿瘤血管系统的宽窗孔和缺乏淋巴引流。然而，EPR 效应被认为是导致临床试验结果异质性的异质现象。通过采用主动靶向策略，人们付出了广泛的努力来提高纳米医学在更大的患者队列中的结果。然而，主动靶向 NPs 通过 EPR 效应在肿瘤中积累，因此无法达到令人信服的治疗效果。通过提高对肿瘤微环境 (TME) 的理解以及 NPs 与其不同成分的机械相互作用，这些障碍正在逐渐消除。在这篇综述中，我们提供了对过去药物靶向问题、TME 再造的当前趋势以及克服过去障碍的未来影响的详细见解。在这方面探索的策略包括使用伴随诊断和调节与全身给药 NP 及其与生物大分子相互作用相关的蛋白质电晕。