A diversity-oriented methodology to customize cardiac RNAi-based nanomedicines (BBT-News)


A diversity-oriented methodology to customize cardiac RNAi-based nanomedicines

The development of a step-wise screening strategy can provide further insights into nano-formulation design and optimization, advancing the era of RNAi therapeutics to treat myocardial ischemia diseases.

Myocardial infarction (MI) remains the most severe clinical presentation of coronary artery disease, in which the acute occlusion can result in liquefactive necrosis of myocardial tissue, whereas the heart itself lacks intrinsic capacity for self-repair, leading to cardiac dysfunction and heart failure.

According to the latest guidelines from the European Society of Cardiology (ESC), patients with MI may receive pharmacotherapy and immediate reperfusion strategy within 24 h post ischemia. However, due to the intricate nature of cardiac vasculature, it remains a notable absence of specific pharmacological interventions recommended for distinct cardiac conditions, such as type 2 MI.

RNA interference (RNAi) therapeutics represents a novel class of pharmaceutical drugs for gene therapy, differing from traditional therapeutic approaches. RNAi is almost applicable to all classes of molecular targets by interfering the target mRNA via the RNA-induced silencing complex machinery. Yet, the identification of potent RNAi therapeutics for ischemic heart disease remains limited by the compound collections and trivial formulations screen process, underscoring crucial challenges for efficient nano-formulation design and optimization.

In a new study published in Nature Communications, UMCG researchers led by Prof. Hélder A. Santos have investigate the effects of different compounds on the nano-formulation fabrication within a polysaccharide-based framework. The authors developed a generalized diversity-oriented strategy by combining high-throughput microfluidics system, step-wise nano-formulation screen and computational interpretated decision-making methods.

“As polysaccharide-based non-viral nanoparticles for siRNA has garnered growing attention over the years, understanding how different cationic compounds interact with anionic polysaccharide may provide insights into tailored the nanoparticle’s design principle. And if we make guidance on concomitantly using experimental techniques and computer algorithms, that will expedite the pace for customized RNAi-based nanomedicines,” says Han Gao, a doctoral Ph.D. candidate in Prof. Santos’ group and the first author of the study.

A collaborative study

This work proposes a nano-formulation design strategy for polysaccharides, resulting in the identification of specific nanosystem for achieving cardiac gene silencing in a clinically relevant myocardial ischemic/reperfusion injury animal model. To achieve this, researchers with expertise in different areas contributed to the valuable findings within the reported study.

For example, Professor Dan Peer, the director of the Laboratory of Precision NanoMedicine at Tel Aviv University, provided the in-house ionizable lipids that were used in the screening pool for ionotropic gelation with polysaccharide. An automated high-throughput microfluidics platform was applied to facilitate the screening process for targeted gene intervention in a step-wise manner, which was designed and created by Professor Ming Ma at the Shanghai Institute of Ceramics. And, Professor Hélder A. Santos, the senior and leading author of the paper, with a long research expertise in nanomedicines’ research, provided with the foundations for this project and the design principles for combinatory nano-formulation screen and insights for efficient nano-formulation identification and optimization, which can be applyied for straightforward guidelines in the development of RNAi-based nanomedicines in the future.

“What we were try to with this study was to investigate the crucial parameters for siRNA delivery, so that the generated knowledge can be further transferable to a wider scenario in pioneering precision cardiac therapy. In the future, we would expand the methodology on different polysaccharides and dataset for assessment, aiming to advance RNAi-based nanomedicines towards clinical applications,” Han Gao and Prof. Santos say.

The article is available free of charge at https://doi.org/10.1038/s41467-024-49804-x

Contact information:                                                                           

Hélder A. Santos
[email protected]
Building 3215 (FB40), 1317
9713 AV Groningen, the Netherlands