Abstract Systemic Lupus Erythematosus (SLE) is an autoimmune disease that typically affects multiple organs. The prevalence ranges from 20 to 150 cases per 100,000 population worldwide and appears to be increasing as the disease is recognized more readily and survival increases. Although drug therapies for SLE have made some progress in recent years, the 10-year survival rate is only about 70% in African-Americans and Hispanics. Moreover, current therapy may be associated with severe side effects and remain a major concern. Therefore, safer and more effective therapeutics are urgently needed. Nucleic acids such as small interfering RNA (siRNA), microRNA (miRNA), and microRNA antagonists (antagomiRs) possess broad therapeutic potential. We recently found that microRNA inhibitors consisting of antagonists targeting specific microRNAs could significantly suppress the inflammatory response and reduce the inflammatory infiltrate in a chimeric mouse model of SLE. Although many delivery techniques (e.g. viral vectors, nanoparticles, electroporation) have been developed, capsid size constraints and poor dose/composition control pose major limitations. Safety of viral vectors and low cell viability and delivery efficacy of non-viral methods are also concerns. Neutrophils (NEs) are the most abundant immune cells which are known to target and penetrate inflamed and infected tissues in vivo. For systemic inflammatory diseases such as SLE that can affect many organs, NEs are ideal carriers of biological drugs since they can be pre-loaded with desired therapeutics and may release their cargo at the inflammatory sites upon excessive activation by concentrated inflammatory cytokines in the form of neutrophil extracellular traps (NETs). To achieve this goal, we have developed a novel nanochannel electroporation (NEP) biochip technology that can deliver precise amounts of a variety of nucleic acids and other agents into live cells without causing cell death. The following are our specific aims: Specific Aim 1: Application of neutrophil-mediated NF-ĸB siRNA delivery for SLE therapy in a murine lupus model. Specific Aim 2: Feasibility of human neutrophil mediated microRNA inhibitors delivery as therapeutic in SLE.