Modular Bioorthogonal Lipid Nanoparticle Modification Platforms for Cardiac Homing.

Area of Science:

• Biotechnology
• Nanomedicine
• Protein Engineering

Background:

• Lipid nanoparticles (LNPs) are crucial for therapeutic payload delivery but lack inherent tissue-homing capabilities.
• Current targeting strategies for LNPs to non-liver tissues involve complex covalent modifications, hindering large-scale production.
• Extracellular vesicle (EV) mimetics offer potential but require advanced modification for specific tissue targeting.

Purpose of the Study:

• To design and validate a novel modular artificial membrane-binding protein (AMBP) platform for postformation LNP modification.
• To enable targeted delivery of LNPs to specific tissues, overcoming limitations of current methods.
• To explore the therapeutic potential of AMBP-modified LNPs for cardiac disease treatment.

Main Methods:

• Development of a two-module AMBP system: a membrane anchor (scGFP and polymer corona) and a functional module (cardiac fibronectin homing sequence).
• Utilized bioorthogonal chemistry for facile coupling of protein modules to create the AMBP.
• Assessed LNP uptake in fibronectin-rich cells under static and shear stress conditions.
• Evaluated AMBP-modified LNP localization in zebrafish hearts.

Main Results:

• AMBP-modified LNPs showed a 20-fold increase in C2C12 cell uptake under static conditions.
• A 10-fold increase in uptake was observed under physiologically relevant shear stresses.
• No loss of cell viability was detected in AMBP-modified LNP treated cells.
• Targeted localization of AMBP-modified LNPs within zebrafish hearts was successfully demonstrated.

Conclusions:

• The modular AMBP platform provides an efficient strategy for modifying LNPs postformation.
• AMBP-modified LNPs exhibit enhanced cellular uptake and targeted tissue localization.
• This smart vector technology holds significant promise for targeted drug delivery, especially in treating cardiac diseases.