Wang Yi, Qian Min, Xie Yibo, Zhang Xiaoyi, Qin Yanhui, Huang Rongqin
Center for Advanced Low-dimension Materials, State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201600, China.
School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, Shanghai 201203, China.
Fundam Res. 2022 Nov 17;4(6):1639-1649. doi: 10.1016/j.fmre.2022.11.003. eCollection 2024 Nov.
Immunotherapy has been seriously retarded due to inadequate antigen presentation and a tumor cell-dominated immunosuppressive microenvironment (TME). Herein, biodegradable multifunctional mesoporous silica nanoparticles, with dispersed carbon nanodots incorporated into the frameworks, active TKD peptide modification on the surfaces and hydrophobic drug loading in the pores, were prepared for targeted chemotherapy synergized with trans-spatial immunotherapy. The nanoparticles were biodegradable due to nanodot-induced framework swelling, which would (1) kill the in situ tumor cells and promote antigen release by targeted chemotherapy and (2) trigger biodegraded debris involving TKD and CDs to largely adsorb the tumor antigens via π-π conjugation synergized hydrophobic interactions and then massively transport these antigens from the tumor cell-dominated TME to the immune cell-dominated spleen via TKD-mediated small size effects. Thereafter, these antigens can be processed into antigen peptides via TKD-mediated lysosome endocytosis and then activate T cells in the spleen via MHC complex construction and dendritic cell cytomembrane presentation. Therefore, improved immunotherapy with trans-spatial antigen presentation avoided TME immunosuppression, which when synergized with targeted chemotherapy, markedly enhanced the therapeutic outcomes of triple-negative breast cancer.
由于抗原呈递不足和肿瘤细胞主导的免疫抑制微环境（TME），免疫疗法的发展严重受阻。在此，制备了可生物降解的多功能介孔二氧化硅纳米颗粒，其框架中掺入了分散的碳纳米点，表面进行了活性TKD肽修饰，孔中负载了疏水性药物，用于与跨空间免疫疗法协同的靶向化疗。由于纳米点诱导的框架膨胀，纳米颗粒是可生物降解的，这将（1）通过靶向化疗杀死原位肿瘤细胞并促进抗原释放，以及（2）触发包含TKD和CDs的生物降解碎片，通过π-π共轭协同疏水相互作用大量吸附肿瘤抗原，然后通过TKD介导的小尺寸效应将这些抗原从肿瘤细胞主导的TME大量转运到免疫细胞主导的脾脏。此后，这些抗原可以通过TKD介导的溶酶体胞吞作用加工成抗原肽，然后通过MHC复合物构建和树突状细胞膜呈递激活脾脏中的T细胞。因此，通过跨空间抗原呈递改善的免疫疗法避免了TME免疫抑制，当与靶向化疗协同时，显著提高了三阴性乳腺癌的治疗效果。
