Cubosomes with pH-triggered cubic phase transition enable cytosolic mRNA delivery for acute respiratory distress syndrome therapy.
Summary
A virus-mimetic cubosome (VE-CB) undergoes a pH-triggered lamellar-to-cubic phase transition that enhances endosomal escape and enables cytosolic delivery of IL-10 mRNA. In murine ARDS, intranasal mIL-10@VE-CB sustained pulmonary IL-10 expression and attenuated inflammation, supporting a translational platform for inhaled mRNA therapeutics.
Key Findings
- VE-CB exhibits a pH-triggered lamellar-to-bicontinuous cubic phase transition confirmed by SAXS and cryo-TEM.
- The phase transition enhances membrane fusion and endosomal escape, enabling cytosolic IL-10 mRNA delivery.
- In ARDS mice, intranasal mIL-10@VE-CB sustained pulmonary IL-10 (~462 pg/mL), reduced inflammatory infiltration and cytokines, and restored macrophage efferocytosis.
Clinical Implications
If safety and efficacy translate to humans, inhaled IL-10 mRNA could provide targeted anti-inflammatory therapy in ARDS while minimizing systemic exposure, potentially complementing lung-protective ventilation.
Why It Matters
Introduces a structurally engineered delivery vehicle enabling efficient, localized mRNA therapy for ARDS—an area with no approved disease-modifying treatments.
Limitations
- Preclinical animal data without human safety or pharmacokinetic evaluation.
- Long-term durability, dosing optimization, biodistribution, and off-target effects not fully characterized.
Future Directions
Scale-up manufacturing, GLP toxicology and large-animal inhalation studies, first-in-human trials, and comparative studies versus lipid nanoparticles or viral vectors; explore additional anti-inflammatory or reparative mRNA cargos.
Study Information
- Study Type
- Cohort
- Research Domain
- Treatment
- Evidence Level
- V - Preclinical in vivo and in vitro experimental evidence supporting a therapeutic concept.
- Study Design
- OTHER