Botulinum neurotoxin serotype A (BoNT/A) is a bacterial di-chain protein containing a protease light-chain which cleaves synaptosomal-associated protein of Mr = 25 k (SNAP-25), a protein essential for neuronal exocytosis; this produces prolonged, but ultimately reversible, abolishment of neurotransmitter release. The retargeting of a BoNT/A-derivative to sensory neurons involved in heightened pain sensation is a potential therapeutic strategy for the treatment chronic pain. The development of such a therapeutic is, however, a complex multi-step process dependent on the identification of suitable cell-surface target receptors, functional expression of appropriate targeting ligands, and the employment of an effective means of conjugating the latter to a binding domain-deficient BoNT/A core-therapeutic. An extensive literature research was conducted which identified both transient receptor potential vallinoid 1 (TRPV1) and tyrosine kinase A (TrkA) as promising target candidates and, furthermore, a spider-venom peptide (double-knot toxin) and nerve-growth factor (NGF) as respective means by which to target them. Two published approaches for the conjugation of targeting ligands to the core-therapeutic were initially assessed: conventional protein fusion and “protein stapling” technology. Comprehensive investigation of these strategies highlighted relative advantages and deficiencies; hence, an additional novel method was developed, based on the binding of S. aureus protein A to immunoglobulin G (IgG) antibodies. This latter strategy was optimized to provide a means to couple the core-therapeutic to either antibodies raised against TrkA, or a recombinantly expressed fusion of NGF and fragment crystallizable (Fc) of rabbit IgG. These approaches both culminated in detectable delivery of the protease into target cells, demonstrating the versatility of this innovative technology. However, NGF produced considerably more efficient protease delivery than its IgG counterpart, thereby, highlighting that for effective toxin retargeting the biological activity of the employed ligand is paramount. Consequently, NGF-mediated targeting via TrkA represents a potentially viable strategy for the intracellular delivery of engineered BoNT/A-based pain therapeutics.