Current treatment options for chronic pain are often associated with dose-limiting toxicities, or lead to drug tolerance or addiction. Here, we describe a pain management strategy, based on cell-engineering principles and inspired by synthetic biology, consisting of microencapsulated human designer cells that produce huwentoxin-IV (a safe and potent analgesic peptide that selectively inhibits the pain-triggering voltage-gated sodium channel NaV1.7) in response to volatile spearmint aroma and in a dose-dependent manner. Spearmint sensitivity was achieved by ectopic expression of the R-carvone-responsive olfactory receptor OR1A1 rewired via an artificial G-protein deflector to induce the expression of a secretion-engineered and stabilized huwentoxin-IV variant. In a model of chronic inflammatory and neuropathic pain, mice bearing the designer cells showed reduced pain-associated behaviour on oral intake or inhalation-based intake of spearmint essential oil, and absence of cardiovascular, immunogenic and behavioural side effects. Our proof-of-principle findings indicate that therapies based on engineered cells can achieve robust, tunable and on-demand analgesia for the long-term management of chronic pain.
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We thank L. Scheller for critical comments on the manuscript; A. W. Xie (Welfine Science & Technology) for providing the Bel-Air aroma diffuser; V. Jäggin and T. Lopes for assistance with fluorescence-activated cell sorting; M. Daoud-El Baba, S. Xue and J. Yin for help with animal experiments, and Y. Huang (ChemPartner) for the CCI-based mouse model; D. Bodenham for support with statistical analysis; and M. Müller, P. Saxena and R. Kojima for generous advice. This work was supported by a European Research Council advanced grant (ProNet, no. 321381), by the National Centre of Competence in Research Molecular Systems Engineering, the National Natural Science Foundation of China (grant nos 31522017, 31470834 and 31670869) and the Thousand Youth Talents Plan of China.
Representative 1-minute video of all treatment groups from Fig. 6b,c.
Representative 13-second video of Straub tail and rearing reactions of mice treated with morphine.
Representative epileptic seizure of a CCI-mouse treated with Tramadol at day 7 (with 3 daily injections of 50 mg per kg).
Representative 1-minute video of naloxone-precipitated drug withdrawal effects (AromaCell versus morphine treatment groups; Fig. 7b).
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Nature Biomedical Engineering (2018)