693196 event 1791811915 1791812539 Abdulraouf Abbas
BME PhD Defense Presentation

Date: 2026-10-14
Time: 12pm
Location / Meeting Link: Health Science Research Building 1 (HSRB1) Auditorium / https://emory.zoom.us/j/99247428614

Committee Members:
James E. Dahlman, PhD (Advisor); Hyejin Kim, PhD; Alex Abramson, PhD; Khalid Salaita, PhD; Yoggang Ke, PhD


Title: BEYOND THE CLINIC: Gastrointestinal and Subcutaneous Administration of Lipid Nanoparticles for RNA Delivery and Therapy

Abstract:
Lipid nanoparticles (LNPs) delivering therapeutic RNA are approved for liver disease (ONPATTRO) and vaccination (SPIKEVAX, COMIRNATY), and many additional RNA-LNP programs are advancing in clinical trials, including intismeran autogene (Phase 3, melanoma). Their administration remains confined to intravenous infusion and intramuscular injection, both of which require a clinical visit and both of which constrain which tissues can be reached. Patients prefer orally administered drugs to parenteral ones, and prefer subcutaneous self-injection at home to intravenous infusion in the clinic. We therefore investigated whether two routes available outside the clinic, gastrointestinal and subcutaneous, could circumvent conventional parenteral administration while reprogramming or maintaining the functional biodistribution of RNA. We screened LNPs delivered through buccal, gastric, small intestinal, colonic, and rectal routes against intravenous administration, and found that gastric administration achieved an order of magnitude greater pancreas delivery in rodents than intravenous administration. Gastric dosing of glucagon-like peptide-1 mRNA improved blood glucose regulation in mice, and buccal administration of ovalbumin mRNA produced immunoglobulin G titers equivalent to intramuscular delivery. We next asked whether subcutaneous administration of LNPs is feasible, evaluating a novel spleen-targeting LNP. The particle was tolerated at four times its intravenous maximum tolerated dose and reproduced its intravenous tropism, which required hyaluronidase co-administration. In non-human primates, functional delivery depended on anatomical injection site, with administration in the thigh resulting in significant expression. Having established that subcutaneous delivery is feasible, we screened a new class of novel ionizable lipids across intravenous and subcutaneous routes in parallel, using DNA barcoding. Subcutaneous administration produced, on average, twice the spleen-to-liver delivery ratio of intravenous administration, and the lead formulation identified, further optimized and administered subcutaneously, resulted in greater on-target delivery than a clinically approved LNP administered intravenously. We then performed further process optimization to enable large-scale formulation, establishing batch consistency and freeze-thaw stability. Together, these results suggest that gastrointestinal and subcutaneous administration can expand how RNA is delivered while providing potential alternatives to clinical visits.

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