Abstract：
Insufficient antigen self-presentation of tumor cells and ineffective antigen cross-presentation by dendritic cells (DCs) contribute to diminished immune recognition and activation, which cause resistance to immunotherapies. Herein, we present an ultrasound-activatable in situ vaccine by utilizing a hybrid nanovesicle composed of a thylakoid (TK)/platelet (PLT) membrane and a liposome encapsulating DNA methyltransferase inhibitor zebularine (Zeb) and sonosensitizer hematoporphyrin monomethyl ether (HMME). Upon local exposure to ultrasound, reactive oxygen species (ROS) are generated and induce the sequential release of the payloads. Zeb can efficiently inhibit tumor DNA hypermethylation, promoting major histocompatibility complex class I (MHC-I) molecules-mediated antigen self-presentation to improve immune recognition. Meanwhile, the catalase on the TK membrane can decompose the tumoral overexpressed H2O2 into O2, which boosts the generation of ROS and the destruction of tumor cells, resulting in the in situ antigen release and cross-presentation of tumor antigens by DCs. This in situ vaccine simultaneously promotes antigen self-presentation and cross-presentation, resulting in heightened antitumor immunity to overcome resistance.
摘要：
肿瘤细胞的抗原自我呈递不足和树突状细胞（DC）的无效抗原交叉呈递导致免疫识别和激活减弱。导致对免疫疗法的抵抗。在这里，我们通过利用由类囊体(TK)/血小板(PLT)膜和包封DNA甲基转移酶抑制剂zebularine(Zeb)和超声增敏剂血卟啉单甲醚(HMME)的脂质体组成的混合纳米囊泡,提出了一种可超声激活的原位疫苗.局部暴露于超声波后，产生活性氧（ROS）并诱导有效载荷的顺序释放。Zeb可以有效抑制肿瘤DNA甲基化，促进主要组织相容性复合物I类（MHC-I）分子介导的抗原自我呈递，以提高免疫识别。同时,TK膜上的过氧化氢酶可以将肿瘤中过表达的H2O2分解为O2，促进ROS的生成和肿瘤细胞的破坏，导致原位抗原释放和DC交叉呈递肿瘤抗原。这种原位疫苗同时促进抗原自我呈递和交叉呈递，从而提高抗肿瘤免疫力以克服抵抗力。
