精准自组装靶向M2巨噬细胞纳米药物介导光热/NO协同治疗肝癌

Compared with monotherapy, the combination therapy of liver cancer treatment can more effectively exert synergistic effects of drugs to enhance the anticancer effect. However, multi-drug delivery nanocarriers currently used in combination therapy have the disadvantages of complicated preparation process, poor reproducibility, and low stability. Based on the previous studies, this project intends to construct Au-BNN6-cM2pep nanomedicine of photothermal/NO synergistic treatment for liver cancer combination therapy. Au-BNN6-cM2pep nanomedicine is performed through the precise and orderly self-assembly of the heat-sensitive NO donor BNN6, photothermal agent gold nanoparticles (Au) and M2 tumor-associated macrophage (TAM) targeting cM2pep peptide using DNA molecular scaffolds. The Au-BNN6-cM2pep nanomedicine specifically recognizes TAM by cM2pep and targets tumor tissue through the homing property of TAM. Once stimulated by the near-infrared light irradiation, this Au-BNN6-cM2pep nanomedicine not only exhibits photothermal conversion to destroy the TAM but also triggers release of NO. Additionally, the Au-BNN6-cM2pep nanomedicine uses photoacoustic imaging for real-time monitoring, effectively guiding NO/photothermal synergy in the tumor site to achieve precise treatment of liver cancer. This project helps to clarify the synergistic anti-cancer mechanism of NO/photothermal therapy, and provides new ideas and strategies for solving the problems of low efficiency of clinical advanced liver cancer treatment.

肝癌治疗的组合疗法与单一疗法相比，能更高效的发挥药物协同作用来增强抗癌效果，但当前用于组合疗法中多种药物的递送纳米载体存在制备工艺复杂、重现性差、稳定性低等缺点。本项目基于已有研究基础，拟将热敏型NO供体BNN6、光热剂金纳米粒（Au）、靶向M2型肿瘤相关巨噬细胞（TAM）cM2pep肽通过DNA分子支架精准有序自组装，构建光热/NO协同治疗的Au-BNN6-cM2pep纳米药物用于肝癌组合治疗。该纳米药物通过cM2pep特异性识别TAM，借助TAM归巢属性靶向肿瘤组织；用近红外光激发纳米药物进行光热转化破坏TAM，同时触发释放NO；并利用光声成像实时监控，在肿瘤部位有效引导NO/光热发挥协同效应，实现对肝癌的精准治疗。本项目的研究有助于阐明NO/光热疗法协同提高抗癌效率机制，为解决临床中晚期肝癌治疗效率低等问题提供新的思路和策略。

用于肝癌治疗的组合疗法与单一疗法相比，可发挥协同作用增强抗癌效果，而目前多治剂纳米递送载体存在制备工艺复杂、重现性差、稳定性低等缺点。因此，本项目拟将光热治剂金纳米棒、NO供体SNAP、M2型肿瘤相关巨噬细胞（TAM）靶向肽M2pep通过Y形DNA分子支架精准有序自组装，构建光热/NO协同介导的肝癌治疗纳米药物Au-SNAP-M2pep。该纳米药物通过M2pep特异结合M2型TAM，借助其归巢属性递送至肿瘤组织深部；利用近红外光触发光热转化破坏M2型TAM，肿瘤及溶酶体酸性环境响应性释放NO，通过光热/NO协同效应高效杀死肿瘤细胞。此外，基于光热转化特性，该纳米药物还可通过超声/光声成像技术实时监控纳米药物的靶向动态，光热成像监控纳米药物体内光热转化效果，引导NO/光热协同治疗肝癌，以提高治疗精准性和有效性，实现肝癌精准诊疗一体化。