Lipid nanoparticles (LNPs) have emerged as a clinically validated platform for cancer immunotherapy; however, challenges remain in optimizing RNA delivery and promoting synergistic immune activation. To address these issues, we developed a modified LNP system that incorporates α-galactosylceramide (α-GalCer), a CD1d-binding glycolipid known to activate invariant natural killer T (iNKT) cells. Through structural optimization, we created the α-GalCer-LNP (G-LNP), which offers three primary advantages over conventional four-component LNPs: (1) enhanced mRNA transfection efficiency due to improved endosomal/lysosomal escape, (2) increased capacity for in vivo DC transfection, leading to robust activation of tumor-specific CD8 + T cells via MHC-I and iNKT cells via the CD1d pathway, and (3) reprogramming of the tumor microenvironment, resulting in a 1.5-fold increase in iNKT cell infiltration and sustained elevation of IFN-γ (>24 h) in lymph nodes. In a TC-1 cervical carcinoma model, G-LNP induced complete tumor regression in 100 % of treated mice (compared to 42.85 % for standard LNP) and provided long-term protection against tumor rechallenge (lasting >100 days). Mechanistic studies showed that G-LNP preferentially targets CD11c + DC in the lymph nodes, facilitating coordinated antigen presentation and innate immune activation. This five-component engineering strategy establishes a versatile platform to enhance the functionality of LNPs for the development of next-generation cancer vaccines.
Qianghui Tang,Qiang Chao,Jianfeng Zhang,Bei Wang,Song Zhao,Kun Yang
Introduction Parasitic worms (helminths) express unique antigenic glycans such as LDN and LDNF, which are absent in mammalian hosts and represent promising vaccine targets. However, free glycans typically elicit weak immune responses and require multivalent delivery and adjuvants to enhance immunogenicity and promote antibody class-switching.Methods Two cetyl-modified glycan antigens (LDN-C16 and LDNF-C16) were chemo-enzymatically synthesized and incorporated into liposomes, either with or without the invariant natural killer T cell agonist α-GalCer as an adjuvant. C57BL/6 mice were immunized subcutaneously. Humoral immune responses were evaluated by ELISA using glycan-BSA conjugates. Cytokine levels were measured in sera from immunized mice. Additionally, the ability of immune sera to recognize native helminth proteins was assessed by Western blotting using protein extracts from adult Schistosoma japonicum worms.Results Liposomal delivery of LDNF, but not LDN, induced potent glycan-specific antibody responses. Adding α-GalCer slightly reduced total antibody titers but enhanced response quality by shifting IgM to IgG, increasing IgG1 and decreasing IgG2b. Liposomal LDNF with α-GalCer also boosted in vivo cytokine responses, increasing IL-4 and IL-10 while maintaining IFN-γ. The induced antibodies showed high specificity for LDNF and effective recognition of native schistosome worm proteins.Conclusion Liposomal presentation of the LDNF epitope strongly enhances immunogenicity. Co-delivery with α-GalCer effectively promotes class-switched IgG responses, modulates cytokine profiles, and improves recognition of native parasite antigens. This liposomal glycan-antigen delivery strategy represents a promising approach for the development of anti-helminth vaccines targeting glycan epitopes.
Ming-Yan Wang,Meng-Xu Yi,Xing-Yu Mo,Shan-Jie Wei,Yu Qiao,Zheng Zhang,Zhao-Liang Su,Hong-Yan Lu
Bronchopulmonary dysplasia (BPD) is a severe lung disease in preterm infants, the abnormal proliferate and differentiate ability of type II epithelial cells (AEC II) is the key to the pathological basis of BPD. Mechanisms regarding abnormal AEC II in BPD remain unclear. The present work investigated the role and mechanisms of invariant natural killer T (iNKT) cells in lung disorder in BPD using public datasets, clinical samples, a hyperoxia-induced BPD mouse model and AEC II-iNKT cells transwell co-culture system. Firstly, we found that the NKT cells development factor IL-15 increased over time in patients with BPD in public databases, and clinically collected peripheral blood NKT cells in patients with BPD were increased. Subsequently, the percentage of iNKT cells increased in hyperoxia group compared with normoxia group, with the highest at P7, accompanied by increased activation with abnormal lung development. The administration of anti-CD1d neutralizing antibody to inhibit iNKT cells could alleviate the abnormal lung development of hyperoxia group mice, while α-GalCer administration could aggravate lung injury in hyperoxia group mice, and adoptive transfer of iNKT cells could aggravate the abnormal lung development in hyperoxia group mice. In addition, to further verify the role of iNKT cells on AEC II, AEC II-iNKT cells co-culture system was established. The presence of iNKT cells could aggravate the abnormal expression of SP-C and T1α under hyperoxia. Meanwhile, RNA-seq analysis showed that ferroptosis-related genes were highly expressed in AEC II co-cultured with iNKT cells under hyperoxia. We further validated the effect of the presence of iNKT cells under hyperoxia environment on AEC II ferroptosis levels, suggested that iNKT cells promote AEC II ferroptosis under hyperoxia, accompanied by decreased expression of SP-C and T1α. Our study found that the recruitment of iNKT cells in the lung may be an important cause of alveolarization disorder in BPD.
危险品化学品经营许可证（带存储）