From Bits to Bonds: High-Throughput Virtual Screening of Ribonucleic Acid Nanocarriers Using a Combinatorial Approach...

Area of Science:

• Biomaterials Science
• Computational Chemistry
• Nanotechnology

Background:

• Developing efficient nanocarriers for RNA delivery is crucial but challenging.
• Traditional screening methods are slow and costly.
• Computational methods face data scarcity and high simulation costs.

Purpose of the Study:

• To introduce a high-throughput virtual screening platform, "Bits2Bonds," for designing novel poly(β-amino ester) (PBAE) nanocarriers.
• To integrate coarse-grained molecular dynamics (CGMD) simulations with machine learning (ML) for optimized siRNA delivery systems.
• To address limitations of traditional experimental screening and purely computational approaches.

Main Methods:

• Developed the "Bits2Bonds" platform integrating CGMD simulations and ML-driven optimization.
• Simulated key delivery challenges like membrane and siRNA interactions using MD-based "challenges."
• Calibrated and validated the computational framework against experimental data (synthesis, characterization, logP, encapsulation, cell assays).

Main Results:

• Successfully designed and virtually screened novel PBAE carriers for therapeutic siRNA delivery.
• Demonstrated the platform's ability to simulate critical aspects of nucleic acid delivery.
• Validated computational predictions with experimental synthesis, characterization, and biological activity data.

Conclusions:

• The "Bits2Bonds" platform offers a powerful tool for the *de novo* design of polymeric siRNA delivery systems.
• This integrated computational approach enables rapid virtual screening and optimization of nanocarriers.
• Facilitates the development of more effective and efficient RNA delivery technologies.