Chronic pain poses major healthcare and economic burdens. The aim of this study was to develop a strategy for pain management by generating a biotherapeutic that requires targeting of soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment protein receptor (SNARE) within the hyper-active sensory nerves. This entailed conjugating nerve growth factor (NGF) and the SNARE-cleaving protease and internalization domains of botulinum neurotoxin A (BoNT/A). The methodology involved genetic fusion and use of a protein stapling technology with a view to replacing the BoNT/A C-terminal neuronal binding subdomain (HCC) with βNGF which is a specific ligand for preferential sensory neuronal targeting. A first generation of BoNT/AΔHCC fused to βNGF was expressed in E. coli and purified. An alternative strategy was also adopted with a view to stapling a recombinant BoNT/AΔHCC-SNAP-25 protein (without the neuronal binding domain) with Vamp2.βNGF produced in E. coli, and a synthetic syntaxin-1 peptide via SNARE complex formation. Treatment of PC-12 cells with BoNT/AΔHCC fused to βNGF did not give any cleavage of intracellular SNAP-25. Failure to redirect BoNT/A protease into PC-12 cells was attributed to inactivity of the βNGF producing E. coli. After a number of attempts, the precursor peptide (Pre-Pro signal peptide) of NGF was identified as an essential element in making a biologically-active βNGF. Encouragingly, after inclusion of this leader peptide sequence into a Vamp2.βNGF construct, it was expressed as an active protein, although with low yield. The latter was addressed by creating a construct encoding a Pre-Pro signal peptide followed by βNGF.Vamp2 in the hope of increasing the yield. Expression of the resultant protein was not attempted. In summary, expression of functionally-active βNGF.Vamp2 was achieved. Further optimization is needed before its conjugation to the BoNT core-therapeutic domains, for redirecting SNARE-cleaving protease into hyper-active sensory nerves.