由于肿瘤细胞摄取和治疗效果有限，聚乙二醇（PEG）修饰的纳米颗粒（NP）经常面临对抗转移瘤和液体肿瘤的有效性降低的问题。为了解决这个问题，正在开发具有增强肿瘤选择性和内化作用的主动靶向脂质体，以改善吸收和治疗结果。使用双功能蛋白对聚乙二醇化纳米颗粒进行功能化并通过非共价附着方法增强靶向药物递送已成为一种有前途的方法。其中，一步和两步定位策略因其简单、高效和多功能性而脱颖而出。一步策略将链霉亲和素标记的抗体或双特异性抗体（bsAb：PEG/DIG × 标记物）直接整合到 PEG 化的 NP 中。该方法利用抗体和 PEG 之间的天然相互作用来实现稳定、特异性结合，从而可以修饰生物素/Fc 结合分子，如蛋白 A、G 或抗 Fc 肽。只需将双特异性抗体与聚乙二醇化纳米粒子混合即可改善肿瘤靶向和内化。两步策略涉及首先在肿瘤细胞表面积累bsAb（PEG/生物素×肿瘤标志物），通过抗体依赖性和补体依赖性细胞毒性触发初始攻击。然后这些 bsAb 捕获 PEG 化的 NP，启动第二波内化和细胞毒性。这两种策略都旨在通过实现特定识别和与疾病特异性标记物或受体的结合来增强聚乙二醇化纳米颗粒的靶向能力。该综述为加速靶向纳米医学开发的临床转化提供了潜在途径。© 2024 Ho 等人。

Polyethylene glycol (PEG)-modified nanoparticles (NPs) often struggle with reduced effectiveness against metastasis and liquid tumors due to limited tumor cell uptake and therapeutic efficacy. To address this, actively targeted liposomes with enhanced tumor selectivity and internalization are being developed to improve uptake and treatment outcomes. Using bi-functional proteins to functionalize PEGylated NPs and enhance targeted drug delivery through non-covalent attachment methods has emerged as a promising approach. Among these, the one-step and two-step targeting strategies stand out for their simplicity, efficiency, and versatility. The one-step strategy integrates streptavidin-tagged antibodies or bispecific antibodies (bsAbs: PEG/DIG × marker) directly into PEGylated NPs. This method uses the natural interactions between antibodies and PEG for stable, specific binding, allowing the modification of biotin/Fc-binding molecules like protein A, G, or anti-Fc peptide. Simply mixing bsAbs with PEGylated NPs improves tumor targeting and internalization. The two-step strategy involves first accumulating bsAbs (PEG/biotin × tumor marker) on the tumor cell surface, triggering an initial attack via antibody-dependent and complement-dependent cytotoxicity. These bsAbs then capture PEGylated NPs, initiating a second wave of internalization and cytotoxicity. Both strategies aim to enhance the targeting capabilities of PEGylated NPs by enabling specific recognition and binding to disease-specific markers or receptors. This review provides potential pathways for accelerating clinical translation in the development of targeted nanomedicine.© 2024 Ho et al.