Abstract It is increasingly recognized that erectile dysfunction (ED) not only affects a man’s sex life but also impacts his relationships and overall psychological well-being. An indication of the importance of erectile function to men is that, in the first 6 years after FDA approval of Viagra® (sildenafil, an oral treatment for ED), 23 million men worldwide filled Viagra® prescriptions, with average annual sales of about $1.7 billion, making it one of the more commercially successful drugs of all time. Sildenafil is a member of the phosphodiesterase-type-5 inhibitors (PDE5i) drug class, which is by far the most commonly prescribed treatment for ED. However, because of side effects, use restrictions (dietary, contraindications), and long time-to-response, a significant percentage of men with ED either discontinue use of PDE5i within the first year or never begin treatment in the first place. Several of the drawbacks associated with an oral/systemic route of administration could potentially be overcome by a local, topical delivery vehicle. However, an aqueous sildenafil citrate solution has not been shown to transdermally penetrate with any significance, as the physicochemical characteristics of these amphoteric drugs make formulation and permeation challenging. With this in mind, our group initiated studies to determine if a proprietary silica particle delivery system developed at Albert Einstein College of Medicine and licensed to Zylö Therapeutics Inc. could act as an effective topical delivery system for PDE5i. Initial studies utilizing first- generation technology demonstrated the feasibility of this approach using nano-sized particles in treating ED in animal models of aging. Since then, a second-generation delivery system has been developed by Zylö for topical delivery of other payloads such as lidocaine and cannabidiol (CBD). The goal of this proposal is to adapt this second-generation technology to sildenafil and optimize it for clinical and commercial translation with the overall hypothesis that topical delivery of sildenafil through the use of a nanoparticle delivery system (sildenafil-NP) can improve erectile function. The proposal will be conducted over the course of one year and will incorporate two specific aims. In Specific Aim 1, Zylö will generate an optimized prototype formulation of sildenafil-NP. This will include modulations to the chemical formulation of the nanoparticles such that a significant increase in the carrying capacity for PDE5i will be realized. In Specific Aim 2, proof-of-principle experiments will be conducted to assess the efficacy of topical application of these second-generation sildenafil-NP in eliciting an erectile response in an animal model of ED resulting from aging. At the conclusion of these proposed Phase I studies, we will have identified a lead sildenafil-NP formulation that is optimized for clinical translation as a topical treatment of ED.