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Abstract

Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory disease with limited durable treatment options, particularly for patients with refractory CRS (rCRS). Increasing evidence implicates microbial imbalance, loss of commensal diversity, and biofilm persistence in CRS pathophysiology; however, few therapies directly target the sinonasal microbiome. This thesis investigates SinoNasal Microbiota Transfer (SNMT), the first endoscopically delivered transplant of intact donor sinonasal microbiota, as a potential therapeutic strategy for rCRS. A three-phase research approach was undertaken. First, a systematic review of randomized controlled trials assessing microbiome-modifying therapies for CRS was conducted. Across antibiotic, probiotic, antimicrobial, and biologically based interventions, few studies incorporated microbial analyses, and none demonstrated consistent improvements linked to microbiota modification, highlighting a significant evidence gap. Second, a first-in-human pilot case series evaluated the feasibility, safety, and preliminary efficacy of SNMT, with or without antimicrobial photodynamic therapy (aPDT) pretreatment. SNMT was safely administered and technically feasible. Two of three SNMT-only recipients experienced clinically meaningful improvement, while aPDT was poorly tolerated. Microbiome analyses showed transient increases in diversity but no durable donor engraftment. Third, an ongoing randomized, double-blind, placebo-controlled trial compared SNMT with saline sham. Interim analyses from the first 50 participants showed no significant differences between treatment arms in the primary endpoint (≥1-point mLK reduction at day 45) or in secondary outcomes including SNOT-22 or olfactory scores. Donor material exhibited higher alpha diversity and enrichment of commensal taxa, but patient microbiota remained individualized and stable over time without treatment-associated shifts. Donor-recipient species sharing was low, and full engraftment was rare. Exploratory modeling did identify microbial features to be early improvement predictors. Together, these findings demonstrate that while SNMT is safe and feasible, it does not confer clinical benefit over sham and does not durably modify the sinonasal microbiome. The stability of the CRS microbiome and limited donor engraftment suggest that more targeted, mechanistically informed microbial therapies may be required to restore sinonasal microbial homeostasis.