Early detection is critical to cancer mortality reductions, and yet the breast imaging clinic visits required for these life-saving early detection programs are inaccessible to disadvantaged, remote, or quarantined populations with limited medical facility access. In fact, breast cancer surveillance programs this year have stalled by as much as 90% versus their pre-pandemic rates, resulting in risky delays in new cancer diagnosis . A saliva-based test for early detection could transform today’s screening paradigms. A promising biofluid for disease detection, saliva can be self-sampled non-invasively, without trained technicians. Saliva is ideal for at-home and other non-clinical site collection; it contains a variety of analytes including exosomes, RNA, DNA, proteins, metabolites, viruses and oral microflora, and is a powerful window on health and disease. Recently, saliva samples have shown better clinical utility vs. nasal swabs for detecting COVID-19 . Mounting evidence exists for oral microbiome links to systemic disease , and salivary biomarkers diagnose complex traits such as pediatric medical conditions, traumatic brain injury, autism, and cancer [4-7]. A commercial saliva-based test for autism is based on 32 human and microbial RNA markers . In many complex trait studies, saliva is frozen as cell-free supernatant. The most prevalent saliva collection and preservation devices, although easy-to-use, preclude effective cell-free RNA and exosome analysis, since saliva samples are treated with lysis reagents resulting in mixed populations of cellular and non-cellular RNAs, increasing noise and damaging performance characteristics. Saliva collection devices that instead use membranes to separate cells suffer from inefficient recovery of critical analytes, either because they lack appropriate preservatives or because they adsorb and therefore lose, a substantial analyte fraction. To enable widespread use for disease detection, new standardized methods are needed to preserve cell-free saliva and retain the integrity of its key constituents for stable transport and downstream analysis. This project extends our past SBIR grant work and our own internal research, to develop an easy-to-use saliva collection and preservation device to stabilize cfRNA and other analytes, enabling us and others to efficiently collect high-quality clinical saliva samples. Using RT-qPCR assays and RNA isotype profiles, we will characterize salivary cfRNA integrity and stability over timelines sufficient for remote collection and transport. Armed with well-characterized RNA decay profiles, we propose an iterative design-of-experiment approach to prototype a versatile device to collect and preserve saliva at room temperature (RT), stabilizing RNA while also preventing cell lysis and bacterial growth. Our device performance validation will use prospectively collected and preserved saliva from >50 women to demonstrate stability for up 72 hours at ambient conditions. This device will standardize methods for collection, stability, and transport of saliva, key to driving virtualized sample collection and healthcare in cancer, viral, and other diagnostics, increasingly critical to a post-pandemic world.