超声响应仿生载氧纳米药物增敏三阴性乳腺癌化学免疫治疗及其机制研究

三阴性乳腺癌（TNBC）侵袭性高，治疗缺乏分子靶标，易产生治疗耐受。我们已证实通过载氧氟碳纳米液滴改善肿瘤乏氧，可逆转TNBC放疗抵抗，协同超声辐照可促进肿瘤内氧气转运，对抗化疗耐药。肿瘤乏氧还进一步加重免疫抑制微环境形成，促进免疫逃逸和免疫耐受。针对乏氧相关的免疫抑制微环境及由此产生的TNBC对PD-L1单抗免疫治疗响应性低、出现脱靶效应的问题，我们利用巨噬细胞膜较强的肿瘤乏氧区域靶向趋化特性，借助膜仿生纳米工程技术构建提升肿瘤免疫应答反应、共载紫杉醇/PD-L1单抗的新型仿生载氧载药体系。以膜仿生及超声辐照的双重靶向作用作为定向递氧递药手段，利用仿生技术长循环、组织相容性好的优势增强体系在肿瘤乏氧区域的高效富集，通过超声触发原位释氧，改善乏氧进而解除免疫抑制，联合化疗激活免疫应答的作用，克服PD-L1单抗和化疗药物的耐药性及脱靶效应，增敏化学免疫疗法治疗TNBC的效果并探讨其机制。

Triple negative breast cancer (TNBC) is highly invasive and lacks targeting molecules for treatment, resulting in chemotherapy tolerance. It has been demonstrated that radiotherapy resistance of triple negative breast cancer can be reversed by alleviating tumor hypoxia via oxygen-loading perfluorocarbon nanodroplets; and that with the assistance of ultrasound irradiation, oxygen can be delivered and distributed within tumor region to fight chemotherapy resistance. In addition, tumor hypoxia promotes tumor immune suppressed microenvironment, resulting in immune escape and immune resistance. Based on the hypoxia-associated suppressed immune landscape of TNBC and the associated low response to anti-PD-L1 antibody immunotherapy, this project intends to construct a biomimetic paclitaxel/ anti-PD-L1 antibody co-loading oxygenated system with the cell membrane coating nanotechnology. The dual targeting ability of macrophage membrane and ultrasound irradiation is used for targeted oxygen delivery. The long system circulation and excellent biocompatibility enhance the efficient enrichment of nanomedicine within the tumor hypoxic area. And in situ ultrasound trigger releases oxygen to modulate tumor hypoxia, which combines chemotherapy to activate the immune response, and overcome the resistance and off-target effects of anti-PD-L1 antibodies and chemotherapeutic drugs. We also explore the effect and mechanism of ultrasound intervention on perfluorocarbon droplets oxygen release to improve the immune microenvironment and then sensitize chemoimmunotherapy for TNBC.