构建二维癌细胞膜杂化纳米载体用于同源靶向增强型产氧-储氧一体化的光动力-免疫联合抗肿瘤治疗

Due to the favourable spatiotemporal selectivity and week tissue invasiveness, photodynamic therapy (PDT) has gradually attracted special attention in the field of tumor therapy. Moreover, PDT can induce “immunogenic cell death”, liberate tumor-associated antigens, and activate the anti-tumor immune response, which would not only effectively eliminate the primary tumor, and suppress abscopal tumor and metastasized tumor. However, the clinical application of PDT is severely limited by hypoxia of tumor tissue. Although in situ oxygen production in tumor by special oxygen-generated nanocarrier can to some extent enhance the therapeutic effect of PDT, the actual oxygen retention in tumor cell is very limited to achieve substantial improvement of the treatment effect because oxygen diffuses around rapidly on account of its low solubility. In recent years, cancer cell membrane camouflaged strategy has been widely concerned and studied by researchers because this strategy can endow nanomedicine with many important functional features, such as immune escape, long-term blood circulation, and homotypic tumor targeting. Hence, we plan to construct biological two-dimensional (2D) nanocarriers using cancer cell membrane based on our previous research work. In brief, photosensitizer Ce6-loaded manganese dioxide nanosheet is attached onto the surface of cell membrane materials by electrostatic interaction to increase the stiffness and stability of 2D membrane nanocarrier, and hemoglobin (HGB) is modified on 2D membrane by biotin-avidin interaction to storage the oxygen generated by degradation of manganese dioxide in the tumor cells, in hope to enhance the practical therapeutic effect of PDT. This project will systematically study the significant breakthrough of 2D cancer cell membrane hybrid nanocarrier in terms of improving oxygen retention efficiency, increasing homologous targeting, and enhancing the anticancer photodynamic-immunotherapy, providing a new idea for the future tumor treatment.

肿瘤光动力治疗具有良好的时空选择性和较小的组织侵袭性，且能够诱导“免疫原性细胞死亡”，并释放出肿瘤相关抗原，激活抗肿瘤免疫效应，不仅能有效地消除原位肿瘤，还能消除转移瘤，逐渐成为研究热点。然而，肿瘤组织乏氧严重限制了该疗法的临床应用。肿瘤原位产氧可在一定程度上增强光动力治疗效果，但由于氧的溶解度很低而快速扩散，实际滞留在瘤内的氧很少，疗效增强并不显著。癌细胞膜伪装策略赋予纳米载体免疫逃逸、长效循环及同源靶向等功能特性，受到研究者的广泛关注。基于此，本项目拟利用癌细胞膜构建二维结构的纳米载体，将装载了光敏剂的二氧化锰纳米片吸附在膜表面增加其刚性和稳定性，并通过生物素-亲和素作用将血红蛋白修饰于膜上，用于储存二氧化锰降解产生的氧气，以增强光动力治疗效果。本项目将系统研究二维结构的癌细胞膜杂化载体在提高氧气滞留效率、增强同源靶向及光动力-免疫联合治疗等方面的重大突破，为肿瘤治疗提供一个新思路。

大部分人工合成的纳米颗粒负载药物进入机体后，会被非特异性清除而影响其治疗效果。为避免这种非特异性清除，提高纳米药物的实际利用率，研究者们将人工合成的多功能纳米载体整合天然的细胞膜，得到的仿生纳米药物不仅保留了人工合成的纳米材料的理化性质，还继承了源细胞的生物学功能，例如免疫逃逸、体内长循环和同源肿瘤自趋化等。因此，本研究从仿生伪装的纳米载体出发，选择易功能化的酚基纳米材料，合成仿生纳米药物用于肿瘤的诊疗一体化研究。. 纳米载体与药物之间的相互作用越强，载药量越高，但同时也带来了药物释放的问题。为了解决这个难题，我们开发了一种以密度泛函理论（DFT）指导的载药策略。借助DFT计算以筛选出与纳米载体结构高度匹配的热休克蛋白90（HSP90）抑制剂--格尔德霉素（GDM），构建可拆卸的纳米平台用于敏化肿瘤归巢的光热疗法。同时，利用载体材料等电点与肿瘤细胞溶酶体pH一致，巧妙地解决了药物有效释放的问题。并通过癌症基因组图谱（TCGA）精确选择了与治疗机理最佳匹配的肿瘤类型。这种DFT指导的载药策略提出了优化载药到纳米载体中的新途径，并最终提高药物利用率和疗效。此外，为了解决纳米药物输送效率普遍较低的问题，我们利用天然、低毒、可再生的木质素材料，通过科学实验和理论计算相结合的方法研究纳米木质素的形成机理以及功能化方法，用于提高纳米药物递送效率，本研究进一步设计了基于LNPs的同源靶向光热纳米制剂并在细胞水平上对其进行初步评估，试验结果表明其具备优良的同源细胞自趋化能力和有效的体外细胞水平治疗效果。.