Abstract：
Carrier-free nanomedicines offer advantages of extremely high drug loading capacity (>80%), minimal non-drug constituent burden, and facile preparation processes. Numerous studies have proved that multimodal cancer therapy can enhance chemotherapy efficiency and mitigate multi-drug resistance (MDR) through synergistic therapeutic effects. Upon penetration into the tumor matrix, nanoparticles (NPs) are anticipated to be uptaken by cancer cells, primarily through clathrin-meditated endocytosis pathways, leading to their accumulation in endosomes/lysosomes within cells. However, endo/lysosomes exhibit a highly degradative environment for organic NPs and drug molecules, often resulting in treatment failure. Hence, this study designed a lysosomal escape mechanism with carrier-free nanomedicine, combining the chemotherapeutic drug, curcumin (Cur), and the photothermal/photodynamic therapeutic drug, indocyanine green (ICG), for synergistic cancer treatment (ICG-Cur NPs) via a facile preparation process. To facilitate endo/lysosomal escape, ICG-Cur NPs were modified with metal-phenolic networks (MPNs) of different thickness. The results indicate that a thick MPN coating promotes rapid endo/lysosomal escape of ICG-Cur NPs within 4 h and enhances the photothermal conversion efficiency of ICG-Cur NPs by 55.8%, significantly improving anticancer efficacy in both chemo- and photo-therapies within 3D solid tumor models. This finding underscores the critical role of endo/lysosomal escape capacity in carrier-free drug NPs for therapeutic outcomes and offers a facile solution to achieve it.
摘要：
无载体纳米药物具有极高的载药量（>80％），最小的非药物成分负担，和容易的制备过程。许多研究证明，多模式癌症治疗可以通过协同治疗作用提高化疗效率并减轻多药耐药（MDR）。一旦渗透到肿瘤基质中，纳米粒子(NPs)预计会被癌细胞吸收，主要通过网格蛋白-冥想内吞途径，导致它们在细胞内的内体/溶酶体中积累。然而,内/溶酶体对有机NP和药物分子表现出高度降解的环境，往往导致治疗失败。因此，本研究设计了一种无载体纳米药物的溶酶体逃逸机制，联合化疗药物，姜黄素（Cur），和光热/光动力治疗药物，吲哚菁绿(ICG),通过简单的制备过程进行协同癌症治疗（ICG-CurNP）。为了促进内体/溶酶体逃逸，ICG-CurNP用不同厚度的金属-酚醛网络(MPN)修饰。结果表明，厚的MPN涂层可在4h内促进ICG-CurNP的快速内/溶酶体逃逸，并将ICG-CurNP的光热转化效率提高55.8％，在3D实体肿瘤模型中的化学疗法和光疗法中，显着提高抗癌功效。这一发现强调了内/溶酶体逃逸能力在无载体药物NP中对治疗结果的关键作用，并提供了实现这一目标的简单解决方案。
