Hydrogels are used in biomedical applications for RNA loading and controlled release

On March 20, 2023, Professor Shi Jinjun’s team from Brigham and Women’s Hospital at Harvard Medical School published a review article entitled “Hydrogels for RNA delivery” in the journal Nature Materials.

RNA-based therapies rely heavily on the use of chemical modifications, ligand conjugation, or non-viral nanoparticles on RNA to improve RNA stability and facilitate intracellular delivery. Unlike molecular-level or nanoscale methods, macroscopic hydrogels are soft, water-expanding three-dimensional structures with remarkable features such as biodegradability, tunable physicochemical properties, and injectability, and their recent application in RNA therapy has attracted widespread attention. Specifically, hydrogels can be designed to precisely control the spatiotemporal control of RNA release, minimizing systemic toxicity and improving efficacy in vivo. This review provides a comprehensive overview of hydrogels for RNA loading and controlled release, describes their biomedical applications, and offers some insights into the opportunities and challenges of the exciting field of RNA delivery.

The corresponding authors are João Conde, Professor Shi Jinjun, and the first authors are Ruibo Zhong, Sepehr Talebian, Bárbara B. Mendes.

So far, siRNA and mRNA therapies have been mainly clinically approved for different diseases, and many others are undergoing clinical trials. Despite the considerable therapeutic potential of RNA, its in vivo delivery has limitations, including enzyme sensitivity, extracellular and cellular barriers, and difficulty in transporting to subcellular compartments with active cargo. Therefore, most clinical-stage RNA therapies are based on chemical modification (phosphate thioate bonding), ligand conjugation (N-acetylgalactosamine (GalNAC)), or non-viral nanoparticle (NP) delivery (lipid NP). Although these methods can improve RNA stability and improve pharmacokinetics, they have their own limitations. Hydrogel is composed of a three-dimensional network of water swelling, which has characteristics similar to natural extracellular matrix, biodegradable, adjustable physical and chemical properties, injectability and other remarkable characteristics, making it useful for tissue engineering, drug delivery, cell morphogenesis and other fields. The unique physicochemical properties of hydrogels make them an attractive RNA delivery system. There have been numerous recent efforts to explore the use of hydrogels for RNA delivery, ranging from gene silencing and protein replacement to immunomodulation for a variety of biomedical applications.

Professor Shi Jinjun’s team at Brigham and Women’s Hospital at Harvard Medical School started with the history of hydrogels for RNA delivery, compared in detail the loading methods of RNA in hydrogels, including direct loading of bare RNA and loading of RNA nanocarrier complexes, then further discussed the design of controlled hydrogel release (sustained release or stimulus-responsive release), and finally listed some specific applications of hydrogel-delivered RNA in biomedical applications, ranging from tissue regeneration to cancer treatment. The research discussed in this article shows that hydrogel systems are not only capable of continuous local delivery of RNA (avoiding repeated administrations), but also enable spatial and temporal control of release rates.

Table 1: Clinically approved RNA therapies.

Figure 1: A brief history of hydrogel-based RNA delivery.

Figure 2: Advantages of hydrogels as RNA delivery systems.

Figure 3: Functional hydrogel for RNA loading and delivery.

Figure 4: Hydrogel loaded with bare RNA.

Figure 5: Functional properties of hydrogel controlled-release RNA.

Table 2: Biomedical applications based on hydrogel delivery of RNA.

Figure 6: Biomedical applications based on hydrogel delivery of RNA.

There is an urgent need to further investigate in vivo the properties of RNA-loaded hydrogels such as degradability, clearance, controlled release, and foreign body reactions. It is expected that continuous improvements in hydrogel design and manufacturing will bring these exciting materials closer to the clinical application of RNA therapeutics. (Source: Science Network)

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