美国宾夕法尼亚大学Jacob S. Brenner小组通过加载内源性抗炎脂质的脂质纳米颗粒，实现更安全的非病毒DNA递送。该项研究成果于2025年2月5日在线发表在《自然—生物技术》上。

研究人员表示，脂质纳米颗粒（LNP）在信使RNA（mRNA）递送中的价值已通过2019冠状病毒病（COVID-19）mRNA疫苗得到证明。但如果能够使用LNP递送质粒DNA（pDNA），将带来额外的优势，比如更长期的表达和启动子序列的可用性。然而，pDNA-LNP面临诸多挑战，如毒性和低递送效率。

研究人员展示了pDNA-LNP在未处理小鼠中诱导急性炎症，主要由cGAS–STING通路驱动。受到DNA病毒抑制该通路以促进复制的启发，研究人员将抑制STING的内源性脂质加载到pDNA-LNP中。将硝基油酸（NOA）加载到pDNA-LNP中（NOA-pDNA-LNP）缓解了体内的严重炎症反应，从而实现了更安全的、延长的转基因表达——在第32天的表达量是mRNA-LNP的11.5倍。

此外，研究人员进行了一次小规模的LNP配方筛选，通过迭代优化转基因表达，在体外提高了50倍的表达水平。加载NOA和其他生物活性分子的pDNA-LNP应通过实现更长期和启动子控制的转基因表达，推动基因医学的发展。

附：英文原文

Title: Safer non-viral DNA delivery using lipid nanoparticles loaded with endogenous anti-inflammatory lipids

Author: Patel, Manthan N., Tiwari, Sachchidanand, Wang, Yufei, ONeill, Sarah, Wu, Jichuan, Omo-Lamai, Serena, Espy, Carolann, Chase, Liam S., Majumder, Aparajeeta, Hoffman, Evan, Shah, Anit, Srkzy, Andrs, Katzen, Jeremy, Pardi, Norbert, Brenner, Jacob S.

Issue&Volume: 2025-02-05

Abstract: The value of lipid nanoparticles (LNPs) for delivery of messenger RNA (mRNA) was demonstrated by the coronavirus disease 2019 (COVID-19) mRNA vaccines, but the ability to use LNPs to deliver plasmid DNA (pDNA) would provide additional advantages, such as longer-term expression and availability of promoter sequences. However, pDNA-LNPs face substantial challenges, such as toxicity and low delivery efficiency. Here we show that pDNA-LNPs induce acute inflammation in naive mice that is primarily driven by the cGAS–STING pathway. Inspired by DNA viruses that inhibit this pathway for replication, we loaded endogenous lipids that inhibit STING into pDNA-LNPs. Loading nitro-oleic acid (NOA) into pDNA-LNPs (NOA-pDNA-LNPs) ameliorated serious inflammatory responses in vivo, enabling safer, prolonged transgene expression—11.5 times greater than that of mRNA-LNPs at day 32. Additionally, we performed a small LNP formulation screen to iteratively optimize transgene expression and increase expression 50-fold in vitro. pDNA-LNPs loaded with NOA and other bioactive molecules should advance genetic medicine by enabling longer-term and promoter-controlled transgene expression.

DOI: 10.1038/s41587-025-02556-5

Source: https://www.nature.com/articles/s41587-025-02556-5