LNP-based technology protects and delivers mRNA into cells, but optimizing stability, reducing side effects, and ensuring equitable global distribution remain critical unmet clinical needs [1]. For these purposes, we discover a new series of malonate-based ionizable lipids for intramuscular mRNA delivery. A 1.5- to 3-fold increase in translation efficiency was observed when mRNA was delivered via malonate lipids AS-CL05 and AS-CL09, significantly outperforming vehicles MC3 and SM102. Furthermore, structural optimization of these lipids significantly enhanced mRNA delivery efficiency. Specifically, lipid nanoparticle (LNP) formulations based on lipid AS-CL28, encapsulating wild-type firefly luciferase (FLS-WT) mRNA, exhibited a two-fold increase in neutralizing capacity compared to lipid AS-CL09. Concurrently, lipid AS-CL29-based LNPs encapsulating dengue virus serotype 2 envelope (DENV2 E) mRNA demonstrated superior potency, yielding a 50% plaque reduction neutralization test PRNT50 titer of 7,211, which surpassed the efficacy of both lipids AS-CL28- and AS-CL09-based formulations [2]. In conclusion, these findings highlight the utility of malonate-based lipids for mRNA delivery, establishing their versatility across a diverse range of mRNA payloads.