Human GSDMD is a key mediator of pyroptosis, a pro-inflammatory form of of cell death. GSDMD has a pivotal role in a broad range of diseases, including autoimmune, metabolic and neurodegenerative diseases as well as cancer. Hence GSDMD is an attractive drug target for the treatment of such diseases and excessive inflammation. The present invention provides single domain antibodies (VHH) targeting the oligomerization interface of GSDMD, enabling efficient inhibition of GSDMD pore formation, pyroptosis and IL-1β release. GSDMD targeting VHHs demonstrate binding affinities in the subnanomolar range. GSDMD inhibition is observed following expression of GSDMD nanobodies in the target cell. Importantly, however, recombinant VHHs added to cultured target cells also block cell death. Inhbitition of intracellular GSDMD via extracellular addition of VHHs may be promoted by a mechanism that involves anti-GSDMD VHHs entering through GSDMD pores and subsequent inhibition of additional pore formation.