Granular Hydrogels for Localized Nanoparticle Delivery

Skin diseases represent a significant clinical and socioeconomic burden, yet effective topical delivery of advanced therapeutics remains a major challenge. Nucleic acid–based therapies hold enormous promise for locally modulating gene expression and restoring skin homeostasis, but their translation is limited, among others, by the lack of simple, adaptable, and clinically relevant delivery platforms. Existing systems often rely on complex fabrication steps, fixed formulations, or specialized chemistries, restricting their use as practical, on-demand vehicles for therapeutic delivery. This work focuses on developing a flexible, modular hydrogel platform capable of stabilizing and releasing lipid nanoparticles (LNPs) encapsulating nucleic acids for topical application. The approach builds upon glutathione–poly(ethylene glycol) (GSH–PEG) hydrogels previously designed for protein and small-molecule delivery. This work is based on the hypothesis that exploiting GSH-mediated interactions between the hydrogel network and nanoparticle surfaces can achieve controlled release and enhanced stability of nanoparticles without compromising their biological functionality. Systematic studies on bulk, nanoporous GSH–PEG hydrogels revealed a key trade-off between network porosity and functional ligand density, identifying ligand availability as a critical determinant of nanoparticle retention. Building on these insights, granular macroporous hydrogels were selected as the platform for nanoparticle delivery. To enable their fabrication, a new emulsion-based method, termed T-Drop, was developed, offering a flexible and accessible approach for producing microgels with high monodispersity and precise control over size. The resulting granular hydrogels exhibited tunable architecture, unique dual-scale swelling behavior, and could be lyophilized with optimized excipients to enable long-term storage and rehydration without loss of structural integrity. Loading and release experiments of nucleic acid-encapsulating LNPs demonstrated that GSH–PEG hydrogels preserved nanoparticle structure and function, in contrast to PEG-only controls. Confocal microscopy and cellular uptake studies confirmed that released LNPs remained functional in human dermal fibroblasts and keratinocytes. Together, this work establishes GSH–PEG granular hydrogels as a versatile, scalable, and translational platform for topical delivery of nucleic acid therapeutics. The platform’s simplicity, tunability, and compatibility with clinically relevant nanocarriers highlight its potential as a foundation for future modular gene therapy applications targeting skin and other accessible tissues.

Author dc:creator

• Angeliki Andrianopoulou (21645748)

• Pharmaceutical Sciences
• Biomaterials
• Drug Delivery

Statement dc:rights

• In Copyright
• Open Access after 2028-01-01

DOI dc:identifier

https://doi.org/10.25417/uic.31451827.v1

OAI identifier oai:identifier

oai:figshare.com:article/31451827