Project Grant F30DC023760

SUSTAINED DELIVERY OF SIRNA-LIPID NANOPARTICLES VIA POLYMER IMPLANT FOR VOCAL FOLD SCARRING - PROJECT SUMMARY VOICE DISORDERS AFFECT APPROXIMATELY 30 MILLION AMERICANS ANNUALLY-NEARLY 1 IN 8 ADULTS-AND ARE FREQUENTLY ASSOCIATED WITH VOCAL FOLD (VF) SCARRING FOLLOWING LARYNGEAL INJURY. DYSPHONIA RESULTING FROM VF FIBROSIS SIGNIFICANTLY IMPAIRS COMMUNICATION, QUALITY OF LIFE, AND WORK PRODUCTIVITY. ENDOTRACHEAL INTUBATION IS A COMMON IATROGENIC CAUSE OF VF TRAUMA, INITIATING FIBROTIC REMODELING DRIVEN BY TRANSFORMING GROWTH FACTOR-BETA (TGF) SIGNALING. CURRENT TREATMENTS, INCLUDING INTRALESIONAL STEROID INJECTIONS, PROVIDE ONLY TRANSIENT BENEFIT, REQUIRING REPEATED ADMINISTRATION AND CARRYING RISKS OF ADVERSE EFFECTS. GENE SILENCING OF SMAD3, A KEY MEDIATOR OF TGF- DRIVEN FIBROSIS, REPRESENTS A PROMISING THERAPEUTIC STRATEGY; HOWEVER, CLINICAL TRANSLATION OF SMALL INTERFERING RNA (SIRNA) THERAPIES IS LIMITED BY RAPID DEGRADATION AND POOR LOCAL RETENTION. LIPID NANOPARTICLES (LNPS) IMPROVE INTRACELLULAR DELIVERY OF SIRNA BUT DO NOT ADDRESS THE CHALLENGE OF SUSTAINED LOCAL THERAPEUTIC EXPOSURE. THIS PROJECT PROPOSES TO OVERCOME THESE LIMITATIONS BY DEVELOPING A BIODEGRADABLE POLYMER-BASED IMPLANT CAPABLE OF SUSTAINED, LOCALIZED RELEASE OF SMAD3 SIRNA-LOADED LNPS (SIRNA-LNPS). OUR CENTRAL HYPOTHESIS IS THAT SUSTAINED DELIVERY OF BIOLOGICALLY ACTIVE SIRNA-LNPS WILL MAINTAIN THERAPEUTIC LOCAL EXPOSURE OVER CLINICALLY RELEVANT TIMEFRAMES, ENABLING PROLONGED MODULATION OF FIBROTIC SIGNALING AND MEASURABLE IMPROVEMENTS IN VF FUNCTIONAL OUTCOMES FOLLOWING INJURY. TO TEST THIS HYPOTHESIS, WE WILL PURSUE TWO SPECIFIC AIMS: (1) DEVELOP TUNABLE SIRNA-LNP-ELUTING IMPLANTS AND VALIDATE ANTIFIBROTIC ACTIVITY OF RELEASED SIRNA-LNPS IN VITRO; AND (2) EVALUATE THE IN VIVO FEASIBILITY AND BIOLOGICAL ACTIVITY OF SUSTAINED SIRNA-LNP DELIVERY IN A RABBIT VF INJURY MODEL, BENCHMARKED AGAINST BOLUS DEXAMETHASONE INJECTION USING A MULTIMODAL ASSESSMENT OF VIBRATORY, BIOMECHANICAL, AND HISTOLOGICAL OUTCOMES. COMPLETION OF THIS WORK WILL ESTABLISH A PLATFORM FOR SUSTAINED, LOCALIZED SIRNA DELIVERY IN THE VFS AND PROVIDE FOUNDATIONAL DATA FOR FUTURE THERAPEUTIC OPTIMIZATION. THIS FELLOWSHIP WILL PROVIDE INTEGRATED TRAINING IN BIOMATERIALS-BASED DRUG DELIVERY, RNA THERAPEUTICS, VF WOUND HEALING, MULTIMODAL OUTCOME EVALUATION, AND TRANSLATIONAL OTOLARYNGOLOGY RESEARCH WITHIN AN INTERDISCIPLINARY ENVIRONMENT AT THE UNIVERSITY OF CINCINNATI WITH MENTORSHIP SPANNING BIOMEDICAL ENGINEERING, LARYNGOLOGY, AND VOCAL FOLD PHYSIOLOGY.