Zhu Yining, Yao Zhi-Cheng, Li Shuyi, Ma Jingyao, Wei Christine, Yu Di, Stelzel Jessica L, Ni Bobby Y X, Miao Yang, Van Batavia Kyra, Lu Xiaoya, Lin Jinghan, Dai Yifan, Kong Jiayuan, Shen Ruochen, Goodier Kailei D, Liu Xiang, Cheng Leonardo, Vuong Ivan, Howard Gregory P, Livingston Natalie K, Choy Joseph, Schneck Jonathan P, Doloff Joshua C, Reddy Sashank K, Hickey John W, Mao Hai-Quan
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
Nat Commun. 2025 Jul 1;16(1):5707. doi: 10.1038/s41467-025-61299-8.
Hydrogel materials have emerged as versatile platforms for various biomedical applications. Notably, the engineered nanofiber-hydrogel composite (NHC) has proven effective in mimicking the soft tissue extracellular matrix, facilitating substantial recruitment of host immune cells and the formation of a local immunostimulatory microenvironment. Leveraging this feature, here we report an mRNA lipid nanoparticle (LNP)-incorporated NHC microgel matrix, termed LiNx, by incorporating LNPs loaded with mRNA encoding tumour antigens. Harnessing the high transfection efficiency of LNPs in antigen-presenting cells, LiNx demonstrates substantial levels of immune cell recruitment, antigen expression and presentation, and cellular interaction. These attributes collectively create an immunostimulating microenvironment and yield a potent immune response with a single dose at a level comparable to the conventional three-dose LNP immunization protocol. Further investigation reveals that the LiNx generates not only high levels of Th1 and Th2 responses, but also a distinct Type 17 T helper cell response critical for bolstering antitumour efficacy. Our findings elucidate the mechanism underlying LiNx's role in potentiating antigen-specific immune responses, presenting a strategy for cancer immunotherapy.
水凝胶材料已成为用于各种生物医学应用的多功能平台。值得注意的是,工程化纳米纤维-水凝胶复合材料(NHC)已被证明能有效模拟软组织细胞外基质,促进大量宿主免疫细胞的募集并形成局部免疫刺激微环境。利用这一特性,我们在此报告一种掺入了mRNA脂质纳米颗粒(LNP)的NHC微凝胶基质,称为LiNx,它通过掺入负载有编码肿瘤抗原mRNA的LNP来实现。借助LNP在抗原呈递细胞中的高转染效率,LiNx表现出大量的免疫细胞募集、抗原表达与呈递以及细胞间相互作用。这些特性共同营造出一个免疫刺激微环境,并以单剂量产生与传统三剂量LNP免疫方案相当水平的强效免疫反应。进一步研究表明,LiNx不仅能产生高水平的Th1和Th2反应,还能产生对增强抗肿瘤疗效至关重要的独特的17型辅助性T细胞反应。我们的研究结果阐明了LiNx在增强抗原特异性免疫反应中发挥作用的机制,为癌症免疫治疗提供了一种策略。
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