Self-Assembling Enveloped Virus-Mimicking Particle for Extrahepatic Targeting mRNA Delivery

Area of Science:

• Biomaterials Science
• Nanotechnology
• Molecular Biology

Background:

• Messenger RNA (mRNA) therapeutics require efficient delivery to extrahepatic tissues, a significant challenge.
• Existing viral and virus-like particle (VLP) delivery systems face limitations in safety, immunogenicity, and scalability.
• A need exists for tunable, safe, and scalable delivery vehicles for extrahepatic mRNA therapy.

Purpose of the Study:

• To engineer a novel, bottom-up self-assembling enveloped virus-mimicking particle (EVMP) for efficient extrahepatic mRNA delivery.
• To optimize EVMP composition and structure for enhanced tissue targeting and transfection efficiency.
• To evaluate the therapeutic efficacy and biosafety of EVMPs in preclinical models.

Main Methods:

• Utilized virtual screening via molecular dynamics simulations for particle design.
• Employed directed evolution through key assembling domain mutation for optimization.
• Incorporated N-terminal fatty acylation and adjusted envelope phospholipid composition.
• Tested EVMP delivery efficiency in lung and spleen tissues and in a lung tumor model.

Main Results:

• Achieved high-efficiency mRNA delivery to lungs and spleen.
• Optimized lung-targeted EVMPs transfected 37% of lung cells, including endothelial and immune cells.
• Demonstrated significant suppression of metastatic lung tumor progression using IL-12 mRNA-loaded EVMPs.
• EVMPs exhibited excellent long-term biosafety and tolerability for repeated administration due to minimal immunogenicity.

Conclusions:

• The developed biomimetic EVMP nanoplatform offers a transformative advance in mRNA delivery technology for extrahepatic diseases.
• This platform enables effective and safe mRNA-based therapies with programmable tissue tropism and modular functionality.
• Establishes a generalizable strategy for engineering biomimetic materials for targeted therapeutic applications.