Engineering Polymer-Lipid Integrated Nanoparticles with Quantitative Design Principles for Organ-Selective mRNA...

Area of Science:

• Biotechnology and Nanomedicine
• Drug Delivery Systems
• Molecular Therapeutics

Background:

• Therapeutic mRNA success hinges on effective in vivo delivery systems for organ-selective targeting.
• Current empirical screening methods struggle with the nonlinear relationships between nanoparticle composition and delivery outcomes.
• Achieving precise in vivo targeting of mRNA remains a significant challenge in nanomedicine.

Purpose of the Study:

• To establish a quantitative design framework for engineering organ-targeted mRNA delivery systems.
• To define the formulation-biodistribution relationships of novel polymer-lipid integrated nanoparticles (PLINs).
• To enable precise, organ-selective delivery of mRNA for various therapeutic applications.

Main Methods:

• Integrated an I-optimal design-of-experiments (DOE) strategy with predictive regression modeling.
• Developed a novel PLIN architecture using amphiphilic polyesters and cationic/ionizable lipids, excluding cholesterol and helper lipids.
• Utilized a minimal set of 15 formulations to build predictive models linking formulation parameters to organ-specific mRNA expression.

Main Results:

• Developed predictive regression models (R² > 0.96) quantifying formulation-biodistribution relationships for PLINs.
• Achieved high organ selectivity, with up to 91% lung or 96% spleen targeting through model-guided optimization.
• Identified key physicochemical determinants responsible for the observed organ-tropic behaviors of PLINs.

Conclusions:

• A quantitative, model-driven framework enables the rational design of organ-targeted mRNA delivery systems.
• The developed PLINs offer a versatile platform for precise mRNA delivery across diverse therapeutic contexts.
• This approach establishes generalizable design rules for engineering advanced nanomedicines for targeted therapies.