Precise targeting of effective therapeutic agents represents a holy grail of medicine, as effective therapy necessitates proper tissue distribution. Antibiotics that fail to enter the central nervous system will not successfully treat meningitis, regardless of the intrinsic susceptibility of the causative organism, yet the widespread tissue distribution of potent agents produces unintentional untoward consequences on normal cells. What better system to deliver immunomodulators to a site of inflammation than circulating hematopoietic cells? Such cells endogenously possess the machinery necessary to recognize and interpret the molecular addresses of inflamed tissue and to egress from the vasculature and into the site of incipient inflammation. Loading the cells that will shuttle the biologic cargo poses at least 3 significant challenges to implementation of this system: the immunomodulator must be synthesized in a functional form, be targeted precisely to an intracellular storage compartment that has secretory capacity, and remain functional after agonist-dependent exocytosis.
In principle, Gao et al (page 682) have overcome the first 2 of these hurdles by expressing a soluble form of a tumor necrosis factor (TNF) receptor (sTNFR1) in myeloid cell lines. Quality control in the endoplasmic reticulum stringently regulates protein synthesis, directing misfolded proteins to the proteasome for degradation. Inclusion of a sequence from the transmembrane region of the TNF receptor permitted the nascent TNFR1 construct to enter the secretory pathway, and incorporation of a sorting signal from CD63 diverted the modified sTNFR1 from the constitutive secretory pathway and into an intracellular compartment pending cellular migration to a suitable target site. Unknown, however, are both the functional state of the sTNFR1 in this compartment and the potential for its release by agonist-dependent exocytosis, two properties essential for successful application of this system. The approach described by Gao et al might allow precise delivery of biologically active molecules to the target niche at concentrations that are physiologically relevant, potentially optimizing efficacy and minimizing toxicity.