清华大学喻国灿团队报道了可生物降解脂质改性聚胍硫辛酸聚合物，脂质纳米颗粒增强剂促进mRNA癌症疫苗的有效性和安全性。相关研究成果发表在2024年3月14日出版的《美国化学会杂志》。

基于脂质纳米颗粒（LNPs）的信使RNA（mRNA）疗法在传染病、癌症疫苗和蛋白质替代疗法领域具有很好的潜力。然而，它们的治疗效果和安全性仍然可以通过LNPs制剂的优化来提高。不幸的是，目前的LNPs在翻译过程中活性氧的产生增加，这导致翻译效率降低以及炎症和其他副作用的发生。

该文中，研究人员合成了一种脂质修饰的聚胍硫辛酸聚合物，以制备用于信使核糖核酸疫苗的新型LNPs。获得的G-LNPs通过消除负责翻译抑制和炎症反应的活性氧物种，显著提高负载的mRNA的翻译效率，并在接种后减轻炎症。

体内研究表明G-LNPs@mRNA由于强烈的抗肿瘤免疫反应，疫苗和两剂疫苗显著增加了细胞毒性T细胞的数量和浸润，因此与传统LNPs制备的信使核糖核酸疫苗相比，产生了优越的抗肿瘤效果。通过与免疫检查点阻断协同作用，G-LNPs@mRNA的肿瘤抑制作用进一步增强，表明基于G-LNPs的mRNA疫苗将是对抗癌症的强大和多功能平台。

附：英文原文

Title: Biodegradable Lipid-Modified Poly(Guanidine Thioctic Acid)s: A Fortifier of Lipid Nanoparticles to Promote the Efficacy and Safety of mRNA Cancer Vaccines

Author: Kai Yang, Bing Bai, Jiaqi Lei, Xinyang Yu, Shaolong Qi, Yangfan Wang, Feihe Huang, Zaizai Tong, Guocan Yu

Issue&Volume: March 14, 2024

Abstract: Lipid nanoparticles (LNPs)-based messenger RNA (mRNA) therapeutics have emerged with promising potentials in the fields of infectious diseases, cancer vaccines, and protein replacement therapies; however, their therapeutic efficacy and safety can still be promoted by the optimization of LNPs formulations. Unfortunately, current LNPs suffer from increased production of reactive oxygen species during translation, which leads to a decreased translation efficiency and the onset of inflammation and other side effects. Herein, we synthesize a lipid-modified poly(guanidine thioctic acid) polymer to fabricate novel LNPs for mRNA vaccines. The acquired G-LNPs significantly promote the translation efficiency of loaded mRNA and attenuate inflammation after vaccination through the elimination of reactive oxygen species that are responsible for translational inhibition and inflammatory responses. In vivo studies demonstrate the excellent antitumor efficacy of the G-LNPs@mRNA vaccine, and two-dose vaccination dramatically increases the population and infiltration of cytotoxic T cells due to the intense antitumor immune responses, thus generating superior antitumor outcomes compared with the mRNA vaccine prepared from traditional LNPs. By synergy with immune checkpoint blockade, the tumor inhibition of G-LNPs@mRNA is further boosted, indicating that G-LNPs-based mRNA vaccines will be powerful and versatile platforms to combat cancer.

DOI: 10.1021/jacs.3c14010

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.3c14010