Neutrophil membrane-mediated biomimetic nanoparticle for co-delivery of icariin and siORMDL3 attenuates asthma exacerbated by respiratory syncytial virus

BACKGROUND: Asthma is a chronic inflammatory disorder, and respiratory syncytial virus (RSV) is a major trigger of asthma exacerbation. This study aimed to improve therapeutic efficacy against RSV-exacerbated asthma using neutrophil membrane (NM)-coated nanoparticles (NPs) for co-delivery of orosomucoid-like 3 (ORMDL3)-targeting small interfering RNA (siRNA) and icariin. METHODS: A biomimetic dual-drug delivery system (ORMDL3-targeting siRNA [siORMDL3]/Icariin NPs@NM) was developed by coating NM onto poly(lactic-co-glycolic acid) NPs co-loaded with icariin and siORMDL3. The physicochemical properties, biosafety, cellular uptake, biodistribution behavior, and RNA interference efficiency of the NPs were evaluated. Their therapeutic efficacy was further assessed in vitro and in vivo. RESULTS: The siORMDL3/Icariin NPs@NM exhibited a core-shell structure with NM camouflage, an average diameter of 141.1 nm, and a negatively charged surface. The NPs demonstrated enhanced lung-targeting delivery efficiency with no apparent adverse effects. In vitro, siORMDL3/Icariin NPs@NM significantly improved the viability of BEAS-2B cells treated with interleukin-4 and RSV, while markedly reducing inflammatory cytokine production and oxidative stress markers. In vivo, the siORMDL3/Icariin NPs@NM effectively alleviated airway resistance and improved the inflammatory microenvironment in mice with RSV-exacerbated asthma, with no observable toxicity in major organs. CONCLUSION: siORMDL3/Icariin NPs@NM demonstrated potent anti-inflammatory and antioxidative effects and may serve as an effective dual-drug delivery platform for the treatment of RSV-exacerbated asthma through combination therapy.