br Acknowledgment We thank Professor Yuh Chang Sun for
Acknowledgment We thank Professor Yuh-Chang Sun for providing helpful advice and the Ministry of Science and Technology of the Republic of China for financial support (grants MOST ).
Introduction Past century has witnessed a tremendous increase in life expectancy of the human population, achieved through an overall higher quality of life. One of the major developments and factors contributing to this achievement is the progress in medicinal chemistry, from identification of numerous new drug targets, , ,  to the development of high throughput techniques  and fragment-based tools  for identification of pharmaceutical leads, to synthetic methodologies applied for optimization of drug candidates with the view of improved pharmacokinetics (PK) . However, it remains a great challenge to deliver the drugs to their nominated site of action. Indeed, producing a molecular entity with a desired and even a highly favorable pharmacodynamics effect has become a routine accomplishment of medicinal chemistry. Yet the success rate associated with progression from lab to the clinic remains very low . In large part, translational research for novel drug candidates is troublesome due to systemic distribution of the drug and ensuing side effects. It is understood that delivering the drugs specifically to their site of action is key to higher therapeutic benefits. Indeed, successful tools such as antibody-drug conjugates (ADC) are entering the market and as such represent a major success of medicinal chemistry . However, in-depth analysis of ADC reveals that even with the use of antibodies, arguably the ultimate targeting tools designed by nature itself, a mere 1–2% of the payload is reaching the nominated target,  leaving much room for improvement. Site-specific drug delivery using therapeutic implants offers significant advantages over systemic administration of drugs. Admittedly, pill-based drug administration is more patient-compliant, non-invasive, and most convenient in the majority of cases of drug delivery. However, localized drug delivery is an ultimate tool to achieve the feed of the nominated therapeutic directly to the desired nitric oxide inhibitor and tissues. Successful examples of these tools include cardiovascular implants produced to locally feed anti-proliferative drugs and thus minimize the detrimental overgrowth of the stents with myoblasts . Drug releasing implants based on degradable organic polymers release anticancer drugs locally, when the implants are placed through surgery at the site of brain tumor . Drug eluting beads are successful in delivering drugs to the non-resectable hepatocellular carcinomas . These and other examples of localized drug delivery illustrate the advantages of site-specific drug delivery but also highlight its limitations. Specifically, by design, implants are engineered to perform their nominated function autonomously, but in doing so, these materials offer no control over drug elution and neither patient nor doctors can change the drug prescription from A to B, double the dose of the drug, stop drug elution, or achieve drug elution on demand. These opportunities are highly desired but to date have hardly been achieved. Potential break-through technology poised to overcome these above-mentioned limitations is that of the “substrate mediated enzyme prodrug therapy”, SMEPT (Fig. 1). Learning from the previously established enzyme prodrug therapies (EPT) and specifically the antibody-directed EPT (ADEPT) , development of SMEPT was carried out over the past decade such as to engineer robust and flexible instruments into the design of implantable biomaterials and achieve localized drug synthesis rather than drug delivery , . Envisioned advantages of SMEPT over standard drug-eluting implants are similar to those of ADEPT over ADC (Fig. 2). Most importantly, EPT makes it easy to achieve the synthesis, and therefore the delivery, of combination of drugs, concurrently or in sequence, at the individually nominated doses and times of administration. This is a highly desired opportunity which remains a challenge specifically in the design of conventional drug eluting matrices. Further, EPT offers a drastically increased deliverable payload, achieved through numerous cycles of catalysis performed by each enzyme. Finally, EPT is well suited for the synthesis of short-lived drug molecules for which drug delivery is challenging, such as nitric oxide. In this review, we aim to present the historical developments of techniques that led to the establishment of SMEPT and the state of the art of this methodology. We also briefly discuss the envisioned avenues for subsequent development of EPT as engineered into implantable biomaterials, including the discussion over translational potential of SMEPT.