Non-small-molecule therapeutics for drug addiction: From pharmaco-kinetics modulating to synthetic biology

Drug addiction is a pervasive problem worldwide. It not only affects the abuser's life, but also poses a serious threat to public health. Accordingly, there is a strong demand for the development of novel and effective therapies for drug addiction. Considering that small-molecule drugs have only had limited success, there is great interest in developing alternative strategies that extend the reach of small-molecule-based therapies. The antibody-based trapping approach and the enzyme catalytic strategy have been considered as promising ways to reduce the euphoria of drug users by altering drug pharmacokinetics and decreasing drug concentrations in the central nervous system. However, these biological macromolecules are generally unstable and their in vivo half-lives are short. With the rapid development of gene editing technologies, it is possible to perform ex vivo gene therapy for the long-term and stable delivery of enzymes and other effector proteins, which could free abusers from frequent injections of therapeutics. By constructing programmed gene switches that regulate spatiotemporal gene expression in response to illicit drugs, this perspective proposed the concept of preventing drug addiction by the drug itself. This strategy enables the controlled release of therapeutic proteins in vivo and is expected to improve patient safety and compliance. This will open up new opportunities for next-generation medicine and hold great promise for expanding our ability to treat drug addiction.