文献类型：期刊文献

英文题名：Improving nanochemoimmunotherapy efficacy by boosting "eat-me" signaling and downregulating "don't-eat-me" signaling with Ganoderma lucidum polysaccharide-based drug delivery

作者：Pang, Guibin[1];Wei, Siqi[1];Zhao, Jian[1,3];Wang, Fu-Jun[2,3,4]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, 130 Meilong Rd, Shanghai 200237, Peoples R China;[2]Zhejiang Fonow Med Co Ltd, New Drug R&D Ctr, 209 West Hulian Rd, Dongyang 322100, Zhejiang, Peoples R China;[3]East China Univ Sci & Technol, ECUST FONOW Joint Res Ctr Innovat Med, 130 Meilong Rd, Shanghai 200237, Peoples R China;[4]Shanghai Univ Tradit Chinese Med, Inst Chinese Mat Med, 1200 Cailun Rd, Shanghai 201203, Peoples R China

年份：2023

卷号：11

期号：48

起止页码：11562

外文期刊名：JOURNAL OF MATERIALS CHEMISTRY B

收录：;EI(收录号：20234815110160);WOS:【SCI-EXPANDED(收录号:WOS:001107288600001)】；

基金：This work was supported by the National Natural Science Foundation of China (Grant No. 81571795 and 82104099), and also by Zhejiang Fonow Medicine Co., Ltd (Grant No. F100-42106). The authors thank Mr Jin Lei and Mr Shulei Zhang for insightful discussion of academic topics.

语种：英文

外文关键词：Antigen-antibody reactions - Cell death - Cell membranes - Cell signaling - Controlled drug delivery - Signaling - T-cells - Targeted drug delivery - Tumors

摘要：To address the challenges posed by low immunogenicity and immune checkpoints during cancer treatment, we propose an alternative strategy that combines immunogenic cell death (ICD) effects with CD47/SIRP alpha blockade to reactivate phagocytosis of tumor cells by macrophages with polysaccharide-based drug delivery. In this study, the EGFR inhibitor gefitinib was identified as a novel CD47 modulator, which promoted the translocation of CD47 molecules from the cell membrane to endosomes through the EGFR-Rab5 pathway, leading to reduced cell surface CD47 levels and limiting interaction with SIRP alpha. Based on this finding, we developed prophagocytic mixed nanodrugs to enhance macrophage phagocytosis by encapsulating ICD inducer doxorubicin and CD47 inhibitor gefitinib with immunostimulatory polysaccharides from Ganoderma lucidum. This approach downregulated cell surface CD47 expression to attenuate "don't-eat-me" signaling, while increasing doxorubicin accumulation in tumors by inhibiting drug-resistance proteins, leading to more exposure of calreticulin and amplifying the "eat-me" signaling. In vivo experiments demonstrated that this approach significantly suppressed intraperitoneal tumor dissemination, reversed doxorubicin-induced weight loss, and effectively induced macrophage polarization, dendritic cell maturation, and CD8+ T cell activation. These findings highlighted the significant potential of our macrophage-centered therapeutic strategy using polysaccharide-based nanocarriers and provided new perspectives for chemoimmunotherapy.