Myricetin-a flavonoid capable of inhibiting the SNARE complex formation in neurons-reduces focal sweating after skin-application when delivers as encapsulated in lipid nanoparticles (M-LNPs). The stability of M-LNP enables efficient delivery of myricetin to sudomotor nerves located underneath sweat glands through transappendageal pathways while free myricetin just remained on the skin. Furthermore, release of myricetin from M-LNP is accelerated through lipase-/esterase-induced lipolysis in the skin-appendages, enabling uptake of myricetin by the surrounding cells. The amount of sweat is reduced by 55% after application of M-LNP (0.8 mg kg-1) on the mouse footpad. This is comparable to that of subcutaneously injected anticholinergic agents [0.25 mg kg-1 glycopyrrolate; 0.8 U kg-1 botulinum neurotoxin-A-type (BoNT/A)]. M-LNP neither shows a distal effect after skin-application nor induced cellular/ocular toxicity. In conclusion, M-LNP is an efficient skin-applicable antiperspirant. SNARE-inhibitory small molecules with suitable delivery systems have the potential to replace many BoNT/A interventions for which self-applications are preferred.