2025 Theses Doctoral

Nanomedicine for Transmucosal Delivery of Drugs and Genome Editors

Ding, Suwan

Transmucosal delivery—via oral and intranasal routes—offers a compelling alternative to injection-based administration of biologics, enhancing patient compliance, enabling site-specific action, and reducing systemic toxicity. However, mucosal surfaces present significant physiological barriers to large molecules, including enzymatic degradation, mucus entrapment, and limited epithelial permeability. This dissertation presents nanomedicine-based strategies for non-invasive delivery of gene editors, small molecules, and peptide therapeutics across mucosal barriers, validated through preclinical studies that span genome editing, anti-inflammatory therapy, and metabolic disease intervention.

To enable oral gene editing, we developed a β-glucan-coated polyplex nanoparticle designed to overcome gastrointestinal degradation and target gut-associated lymphoid tissues (GLATs) via Dectin-1–mediated uptake. The formulation exhibited strong mucosal stability, plasmid protection, and cellular uptake in vitro. In vivo, it achieved intestinal transgene expression and functional genome editing in CRISPR-reporter mice. Mechanistic studies confirmed its selective uptake by M cells and immune cells in Peyer’s patches, offering a promising strategy for GALTs-specific gene modulation without injections.

For inflammatory bowel disease (IBD), we synthesized fluoxetine–PEG conjugates to enhance local gastrointestinal retention and minimize systemic exposure. Multi-arm PEG scaffolds improved mucosal stability and boosted serotonin transporter binding. In DSS-induced colitis models, oral PEG–4–FLX significantly reduced weight loss, colon shortening, and histological inflammation. These results highlight the value of rational conjugation chemistry to reengineer systemically active drugs for targeted, safer anti-inflammatory therapy within the gut.

To treat obesity through central nervous system pathways, we developed an intranasal polymeric nanoparticle for delivery of GLP-1 receptor agonists. This platform bypassed the blood–brain barrier via olfactory transport, enabling selective accumulation in specific brain regions. In diet-induced obese mice, treatment led to sustained weight loss, reduced food intake, and promising glycemic control. The approach minimized peripheral exposure and side effects, supporting intranasal delivery as a feasible, non-invasive strategy for targeting brain circuits in metabolic disease.

Collectively, this dissertation demonstrates the potential of nanomedicine-enabled transmucosal delivery to administer a diverse array of therapeutic modalities without injection. By integrating rational design with disease-specific needs, this work provides a foundation for translating non-invasive gene and drug therapies to the clinic across inflammatory, genetic, and metabolic disorders.