Administration of Epinephrine (Epi) using an intramuscular autoinjector (EAI) is the primary first aid treatment available for the management of anaphylaxis in the community of many countries. Around 1 in 10 patients require a second EAI within 5-15 min. Previously, we successfully developed rapidly disintegrating sublingual tablets (RDST) containing Epi microcrystals that exhibited comparable in vivo pharmacokinetics to that of EAI to overcome the drawbacks of EAIs. To further advance these RDST, we hypothesized that synthesizing Epi nanoparticles (Epi-NP) for incorporation into our previously developed Epi RDST could prolong Epi release sufficiently to eliminate the need for a second dose. Therefore, the primary objective of this research was to synthesize various Epi-NP with different drug loads and investigate their release profiles and sublingual permeability. In vitro release and ex vivo permeability studies were performed using synthetic dialysis membranes and excised porcine sublingual membranes, receptively. The release and permeation of Epi from both NP with adsorbed Epi (Ads Epi-NP) and NP with encapsulated Epi (Enc Epi-NP) were significantly slowed down and achieved continuous control over 8 hours. At 60% Epi load, Epi release from Enc Epi-NP was significantly lower than from Ads Epi-NP, however, the cumulative permeated Epi was only significantly lower towards the end of the experiment, suggesting similar control over Epi permeability. Finally, visualization of NP permeation across the sublayers of the sublingual mucosa confirmed the formation of a temporary depot for Epi and maintained Epi release for several hours post-administration. The results from this study demonstrate for the first time the short-term sustained-release potential of the sublingual route to overcome the need for a second dose.