Nitric oxide (NO) is a gaseous transmitter with a wide range of physiological functions. Herein, a transdermal patch with a non-aggressive drug delivery manner using high specific surface area porous aromatic frameworks (PAFs) as carriers is designed. With the surface-modified PAF-1, the internal hydrophobicity allows the equally hydrophobic NO donor, i.e. isoamyl nitrite (IAN), to be encapsulated into PAF-1’s pores. The external hydrophilicity allows the PAF-1 particles to be mixed well with the water-soluble polymer matrix, polyvinyl alcohol (PVA), to prepare a mixed-matrix membrane (MMM) of IAN@PAF-1-mPEG/PVA as a patch. The MMM could release the NO very fast to ~ 14.3 μM in 6 min under a simulated environment. NO could also enter the bloodstream through the mice’s skin under thermal stimulation and could increase NO concentration in the blood of mice to ~ 4.8 μM in 25 min.