抗肿瘤联合治疗纳米递送系统是当前纳米药物研究的热点领域。然而，当联合递送的药物的作用靶点分别位于肿瘤细胞内和细胞外时，则须发展可序贯式递送药物（sequential drug delivery）的纳米系统。本项目在前期工作基础上，构建新型可序贯式递送药物的核-卫星（Core-Satellite）纳米系统，该系统具有肿瘤微环境pH快速响应（< 3 min）和电荷快速“转换（conversion）”（< 3 min）的特性，药物分级递送的准确性和效率显著优于已有文献报道。以黑色素肿瘤为模型，该系统可将抗血管生成治疗和抗血管生成拟态（vasculogenic mimicry，VM）治疗有机结合，有效克服临床肿瘤抗血管生成药物因VM导致治疗抵抗的限制。本项目构建的核-卫星纳米系统可为序贯式纳米药物递送系统的设计提供借鉴，相关研究国内外未见报道，具有很高的创新价值。

“Combo” nanosystem that enables co-delivery of multi-modal therapeutics for efficient and targeted cancer therapy is one of the hottest field in nanomedicine research. However, the development of sequential delivery system is urgently required when the targets of the therapeutics locate in the extracellular and the intracellular compartment of tumor cells, respectively. In this proposal, a new Core-Satellite nanosystem is smartly engineered for sequential drug delivery. The nanosystem is super-sensitive (< 3 min) to the pH of tumor microenvironment, which triggers the rapid drug release for extracellular target and thereafter quick charge conversion (< 3 min) for uptake by tumor cells for intracellular target therapy. Both the accuracy and the efficiency of the first- (extracellular target) and second- (intracellular target) order drug delivery are remarkably superior to those reported in the literature. Using melanoma as model, the Core-Satellite nanosystem can well combine the antiangiogenic and anti-vasculogenic mimicry (VM) cancer therapy, and break through the resistance limitation of clinic antiangiogenic agents due to the VM. Our innovative investigation will provide new theoretical ideas and guidance in the development of sequential drug delivery system, and novel antiangiogenic, and anti-VM therapeutic strategy.