杂合膜包金纳米棒光热促进多发性骨髓瘤免疫治疗的研究

Despite the advent of novel therapies and improvements in survival, multiple myeloma (MM) remains an incurable disease and most MM patients ultimately relapse, which indicates that new agents and novel treatment strategies continue to be a priority for this disease. Photothermal therapy (PTT) is a high efficiency method for inducing cancer cell apoptosis and necrosis by thermal effect，inducing promote of immune response, which has great potential for use in cancer immunotherapy. Hence, in this project, high efficiency photothermal therapy mediated by a biomimetic nanoparticle is applied to improve immunotherapy against multiple myeloma. RBC-platelet hybrid membrane-coated gold nanorods (PMGNRs) with high stability and characteristic properties of both source cells – the adhesion ability with collagen and blood clot like platelets and the long circulation time like red blood cell, are developed as photothermal agent. A large number of PMGNRs target to microthrombosis that formed after tumor vascular injury by photothermal damage using a self-amplified targeting strategy. PMGNRs-mediated high efficient PTT induce neoantigens release in situ, leading to dendritic cells (DC) maturation. Meanwhlie, the expression of proinflammatory cytokines and chemokines are promoted and immune response activated. Eventually, PTT combined with anti-CD38 antibody (daratumumab) treatment delay tumor growth in vivo. This project provides a reference for the development of MM therapy strategy.

尽管新疗法的出现使多发性骨髓瘤（MM）患者生存期有所改善，但MM仍是一种不可治愈的疾病，大多数骨髓瘤患者最终复发，亟需更有效治疗手段。光热治疗（PTT）通过热效应有效诱导肿瘤细胞凋亡和坏死，并能促进机体对肿瘤的免疫反应，在肿瘤的免疫治疗中有较大应用潜力。因此，本项目将仿生纳米粒介导的高效PTT用于促进多发性骨髓瘤的免疫治疗。本项目选用金纳米棒作为光热载体，包覆血小板红细胞杂合膜，构建杂合膜包金纳米棒（PMGNRs），使其同时具有类似血小板与胶原和凝血块的粘附能力和类似红细胞的长循环能力。光热损伤诱导肿瘤内血管微血栓形成，吸引PMGNRs通过自放大靶向效应靶向聚集于肿瘤部位，再次光照即可杀灭肿瘤细胞。此外，PMGNRs介导的高效PTT可促使肿瘤抗原释放、树突状细胞成熟、促炎细胞因子和趋化因子表达，促进抗CD38抗体免疫治疗有效抑制肿瘤复发或转移。本项目为MM治疗策略提供了新的思路。

本研究将金纳米棒作为光热载体，包覆血小板红细胞杂合膜，成功构建杂合膜包金纳米棒（PMGNRs），其同时具有较高稳定性、类似血小板与胶原和凝血块的粘附能力、类似红细胞的长循环能力、及较好生物安全性。光热损伤肿瘤内血管后微血栓形成，PMGNRs通过自放大靶向效应靶向聚集于肿瘤部位。高效的光热效应（PTT）不仅直接杀伤肿瘤细胞还能促进免疫应答，联合达雷木单抗免疫治疗有效抑制小鼠多发性骨髓瘤（MM）肿瘤生长。本研究通过探究新治疗方法为临床救治MM患者提供新思路有重大意义。