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.