Nitric oxide (NO) is a therapeutic implicated for the treatment of a variety of pathologies that afflict lymphatic tissues, ranging from cardiovascular and infectious diseases to cancer. Existing technologies available for NO therapy, however, provide poor bioactivity within lymphatic tissues. In this work, we address this technology gap with a NO encapsulation and delivery strategy leveraging the formation of S-nitrosothiols on lymphatic-targeting Pluronic-stabilized, poly(propylene sulfide)-core nanoparticles (SNO-NP). In an in vivo lymphatic delivery murine model, we evaluated the lymphatic versus systemic delivery of NO resulting from intradermal administration of SNO-NP, examined signs of toxicity systemically as well as localized to the site of injection, and benchmarked against a commonly used commercially available small molecule S-nitrosothiol NO donor. We found SNO-NP to facilitate the controlled and sustained delivery of NO to LN, in contrast to a small molecule NO donor. As a result, over 72 hr post injection, SNO-NP increased the delivery of SNO to LN by two orders of magnitude. Treatment also resulted in dramatic increases in the abundance of LN-resident cells despite no apparent LN cell death associated with treament nor signs of systemic toxicity after administration. Since NO has shown in vitro/in vivo promise in lymphatic-related cancer therapy and infectious disease applications but has been unable to progress due to delivery-related challenges, with further development this NO delivery technology has the potential to advance such NO-based therapeutic appraoches through enhancement of lymphatic targeting.