Stiffness-Gated Cytoplasmic mRNA Delivery Through Engineered Membrane Fusion for Breast Cancer Immunotherapy

Area of Science:

• Biotechnology
• Nanomedicine
• Molecular Biology

Background:

• Traditional lipid nanoparticles (LNPs) exhibit poor lysosomal escape and off-target toxicity, limiting mRNA therapy.
• Existing membrane fusion carriers lack cell specificity, leading to cytotoxicity.

Purpose of the Study:

• To develop a stiffness-gated mRNA delivery platform for enhanced target cell specificity and reduced toxicity.
• To overcome the limitations of current mRNA delivery systems.

Main Methods:

• Engineered a platform (PGC@FM) with a PLGA core and a low-stiffness tumor cell fusion membrane (FM) enriched with unsaturated fatty acids.
• Utilized membrane stiffness differences for selective fusion with low-stiffness target cells and endocytosis in high-stiffness non-target cells.

Main Results:

• PGC@FM demonstrated a 5.2-fold increase in EGFP-mRNA transfection and a 4.2-fold increase in tumor-specific p53-mRNA delivery compared to LNPs.
• Achieved potent tumor suppression and immune activation.
• Non-target cells rapidly degraded internalized PGC@FM, significantly reducing off-target toxicity.

Conclusions:

• The stiffness-gated strategy enables highly selective mRNA delivery by exploiting the biophysical principle of membrane rigidity compatibility.
• This platform offers a promising approach for developing safer and more effective mRNA delivery carriers.