Hyaluronic Acid Nanogels: A Promising Platform for Therapeutic and Theranostic Applications

Abstract

Hyaluronic acid (HA) nanogels are a versatile class of nanomaterials with specific properties, such as biocompatibility, hygroscopicity, and biodegradability. HA nanogels exhibit excellent colloidal stability and high encapsulation capacity, making them promising tools for a wide range of biomedical applications. HA nanogels can be fabricated using various methods, including polyelectrolyte complexation, self-assembly, and chemical crosslinking. The fabrication parameters can be tailored to control the physicochemical properties of HA nanogels, such as size, shape, surface charge, and porosity, enabling the rational design of HA nanogels for specific applications. Stimulus-responsive nanogels are a type of HA nanogels that can respond to external stimuli, such as pH, temperature, enzyme, and redox potential. This property allows the controlled release of encapsulated therapeutic agents in response to specific physiological conditions. HA nanogels can be engineered to encapsulate a variety of therapeutic agents, such as conventional drugs, genes, and proteins. They can then be delivered to target tissues with high efficiency. HA nanogels are still under development, but they have the potential to become powerful tools for a wide range of theranostic or solely therapeutic applications, including anticancer therapy, gene therapy, drug delivery, and bioimaging.

Keywords: controlled release; hyaluronic acid nanogels; nanomedicine; targeted delivery; theranostics.

Figure 1

Strategies for fabricating HA nanogels. Hyaluronic acid (HA) nanogels can be fabricated using a variety of methods, including the following: (1) electrostatic interactions—cationic polymers or inorganic cations can be used to crosslink HA through electrostatic interactions; (2) self-assembly—amphipathic HA can self-assemble into nanogels driven by hydrophobic interactions; (3) chemical crosslinking—HA can be chemically crosslinked using different reactions, e.g., carbodiimide reactions, disulfide bond formation, or the crosslink reactions of methacrylate groups; (4) self-crosslinking—HA modified with covalently linkable groups can form nanogel structures in response to specific stimuli.

Figure 2

Functions of HA nanogels. Hyaluronic acid (HA) nanogels have several unique functions, including the following: (1) improved colloidal stability—HA nanogels can prevent aggregation and precipitation of encapsulated payloads, extending their retention in the circulatory system and limiting nonspecific distribution; (2) lyophilization and reconstitution—HA nanogels can be lyophilized and reconstituted without altering their physicochemical properties or potency of the payloads, improving their shelf life and facilitating product distribution; (3) tumor homing—HA nanogels can accumulate in tumor tissues through passive and active targeting mechanisms, including the enhanced permeability and retention (EPR) effect and receptor-mediated endocytosis; (4) quenching of encapsulated photoluminescent molecules—HA nanogels can quench the photoactivity of encapsulated molecules until they are internalized and destabilized or degraded; this can be used to control the release of payloads in response to specific stimuli or to improve the biocompatibility of photosensitizers.

Figure 3

Potential applications of HA nanogels. Due to their unique properties, HA nanogels have emerged as promising candidates for theranostic or solely therapeutic applications. Their ability to encapsulate a diverse array of therapeutic agents, ranging from small molecule drugs to macromolecular therapeutics, coupled with their responsiveness to external stimuli for controlled release, makes HA nanogels ideal for a wide range of biomedical applications. HA nanogels have been extensively studied in various biomedical fields, including anticancer therapy, gene therapy, targeted drug delivery to specific tissue sites, and bioimaging.