免疫原性细胞死亡：新型个性化纳米放大器的开发与增效机制探索

免疫治疗联合化疗是提高癌症治疗效果的一种新策略，但仍然面临化疗药物免疫刺激性低、易产生抗药性及副作用大等重要问题。为应对这一系列挑战，本项目拟设计制备新型纳米材料作为免疫原性细胞死亡（ICD）的放大器，探索免疫-化疗联用的新机制，拟主要研究三方面的内容： 1）开发普适性的制备新方法，合成具有粗糙表面及可控芬顿活性位修饰的新型纳米颗粒作为ICD放大器；2）调控ICD放大器的芬顿活性，定制针对不同种临床化疗药物和不同肿瘤细胞的个性化ICD放大器；3）利用优选组合，进一步探索纳米放大器产生放大作用的分子机制与信号通路，深入研究纳米颗粒与类芬顿催化剂的结构、活性与ICD放大性能的构效关系。通过本项目的实施，有望建立新颖的ICD纳米放大器平台，率先在分子水平理解纳米材料对免疫化疗联用增效的新机制，不仅为化疗药物的临床应用提供了新思路，更为发展基于纳米材料的化疗-免疫联合疗法提供了物质和理论基础。

Chemo-immunotherapy is a new strategy with improved anti-cancer therapeutic effect. However, many problems exist in this area, such as low immune stimulating efficiency, high resistance and severe side effects of chemotherapeutic drugs. In this project, innovative nanomaterials will be designed to amplify immunogenic cell death (ICD) and the underlying amplification mechanisms will be explored. The specific aims are to, 1) develop a general and novel approach to synthesize versatile ICD nano-amplifiers, i.e., nanoparticles featuring rough surface and controllable Fenton active sites; 2) design customized ICD amplifier for various clinical chemotherapeutic drugs and tumor cells by controlling the nanostructure and Fenton-reaction activity of the amplifiers; and 3) explore the molecular mechanism and signalling pathway of ICD amplification induced by ICD amplifiers designed in this project. The novel nanoparticle platform and ICD amplification pathway discovered in this project provide not only a new way for the clinical administration of chemotherapeutic drugs, but also useful guidelines in the rational design of future nanomedicines for chemo-immunotherapy to further enhance the performance of chemo-immunotherapy.