image: Mn2+ assembles with PTEN mRNA through weak forces rather than electrostatic interactions, facilitating reversible and efficient cellular mRNA release with a rational absolute binding free energies and dissociation constant. Through αPD-L1-modified monocyte-macrophage membrane coating, Mn-NP@PM achieves tumor targeting and utilizes membrane fusion for direct cytoplasmic mRNA delivery and optimizing transportation efficiency.
Credit: ©Science China Press
PTEN is a critical tumor suppressor frequently dysregulated in cancers. While PTEN mRNA delivery offers a promising path for immunotherapy, current systems have bottlenecks, such as electrostatic loading dependency, inefficient cytosolic delivery, and stability issues.
To overcome these challenges, a research team has developed a biomimetic mRNA delivery platform inspired by natural metal-ion coordination and exosome mechanisms. The system employs adjuvant metal ions, particularly Mn2+, to chelate and load PTEN mRNA through mild, non-electrostatic forces. The resulting complex is further encapsulated in a monocyte-macrophage membrane modified with αPD-L1, facilitating tumor targeting and immune evasion.
Key advantages over conventional lipid nanoparticles (LNPs) were demonstrated:
- Improved mRNA Loading – The system achieved 98% loading efficiency versus 95% with LNPs, and reduced the empty carrier rate to only about 10%, compared to 40–80% for LNPs.
- Enhanced Transfection Efficiency – By using membrane fusion to directly deliver mRNA into the cytoplasm, the system bypassed endosomal trapping. This resulted in roughly 2-fold higher delivery in cells and 20-fold higher in tumors.
- Superior Stability – Even after extended storage in both liquid and freeze-dried forms, the system maintained twice the level of protein expression compared to LNPs.
Additionally, through analysis of clinical data, the team linked PTEN expression levels to patient outcomes. They also developed a classification model to help identify patients most likely to benefit from PTEN-based therapy.
This work provides a robust and efficient mRNA delivery platform and strengthens the case for precision immunotherapy in colorectal cancer.
Journal
Science Bulletin