Cubosomes with pH-triggered cubic phase transition enable cytosolic mRNA delivery for acute respiratory distress syndrome therapy.

Interleukin-10 (IL-10) represents a promising anti-inflammatory candidate for acute respiratory distress syndrome (ARDS) treatment, but its clinical application is hindered by short half-life and poor lung exposure when delivered as recombinant protein. We developed virus-mimetic cubosomes (VE-CB) based on vitamin E-derived ionizable lipid and glyceryl monooleate for cytosolic delivery of IL-10 mRNA. The system features a pH-triggered lamellar vesicle-to-bicontinuous cubic phase transition that mimics viral membrane fusion mechanisms. Upon acidification to endosomal pH (5.0-5.5), VE-CB underwent a rapid lamellar vesicle-to-bicontinuous cubic phase transition, as confirmed by small-angle X-ray scattering and cryo-transmission electron microscope. This structural switch enhanced membrane fluidity and fusion capability, enabling efficient endosomal escape. In ARDS mice, intranasal administration of mIL-10@VE-CB achieved sustained pulmonary IL-10 expression (462 pg/mL), significantly reduced inflammatory cell infiltration, decreased pro-inflammatory cytokines, and restored macrophage efferocytosis. The virus-mimetic cubosome platform represents a safe, efficient, and versatile strategy for pulmonary mRNA delivery, offering substantial clinical translational potential for ARDS precision therapy through structure-enabled cytosolic delivery and synergistic anti-inflammatory mechanisms.