Chronic pain, including arthritis, poses a substantial economic and social burden on society. A major unmet need exists for effective, long-lasting and non-addictive safe analgesics. Treatment of chronic pain could be revolutionized by targeted delivery of long-acting secretion blocker into inflammatory cells and/or sensory neurons to inhibit the release of pro-inflammatory cytokines and pain neuropeptides. In this thesis, we selected the interleukin-1 receptor (IL-1R), TNF receptor (TNFR) and CGRP (calcitonin gene related peptide) receptor as specific targets for selective delivery of long-lasting botulinum neurotoxin type D (BoNT/D) protease into immune cells and/or peripheral sensory (but not motor) neurons to cleave SNAREs(N-ethylmaleimide sensitive factor attachment receptors). The latter are essential for the release of cytokines and pain-peptides which play pivotal roles in the pathogenesis of arthritis. To achieve this goal, the receptor binding domain of BoNT/D is replaced recombinantly with an IL-1R targeting ligand [IL-1β (agonist), IL-1 receptor antagonist (IL-1RA)] or an TNFR receptor antagonist (Atsttrin) to yield three novel retargeted BoNT/D based therapeutics (/DIL-1β, /DRA and /D-Atsttrin). These proteins were successfully expressed in E. coli and purified using affinity chromatography with retention of biological activities of their targeting ligands. Not surprisingly, these ligands successfully delivered the BoNT/D protease into cultured immune cells (macrophages) resulting in cleavage of vesicle associated membrane protein 3 (VAMP-3) and inhibition of two important cytokines release (TNF-α and IL-6), much more potently than the non-ligand control protein. Moreover, these therapeutic candidates also entered into cultured dorsal root ganglion neurons, cleaved VAMP-1 and inhibited substance P peptide release, unlike the non-ligand control protein. Thus, for the first time, we have successfully engineered dual-targeting BoNT-derived secretion blockers. Furthermore, we also developed a novel effective delivery strategy using sortase to site-specifically ligate BoNT/D core-therapeutic to CGRP receptor antagonist (CGRP8-37) with ability to inhibit substance P release. Inhibiting the release of pro-inflammatory cytokines and/or pain-peptides by engineered novel biotherapeutics highlights their potential for the treatment of chronic inflammatory pain.