Prodrug-based drug delivery systems: strategic approaches and emerging challenges in targeted therapeutics

Prodrug-based drug delivery systems have emerged as a versatile and promising strategy for overcoming limitations associated with conventional drug formulations, such as poor solubility, low bioavailability, off-target effects, and systemic toxicity. By temporarily modifying active pharmaceutical ingredients (APIs), prodrugs can be engineered to improve therapeutic efficacy and safety profiles. This review aims to critically evaluate the current advancements, challenges, and future directions in prodrug design and delivery, with a focus on strategies that enhance pharmacokinetics, target specificity, and controlled release. Emphasis was placed on studies published over the last decade that discuss innovative prodrug approaches, delivery systems, and nanotechnology applications in drug delivery. The review categorizes prodrug strategies into two major domains: (1) chemical modification, involving covalent linkage of functional groups to alter solubility, lipophilicity, and metabolic stability, and (2) carrier-mediated delivery, employing nanocarriers such as liposomes, polymeric nanoparticles, dendrimers, and micelles to improve targeted delivery and minimize systemic exposure. While significant progress has been made, critical issues persist-such as prodrug instability, premature release, and potential toxicity. Recent innovations including rational linker design, stimuli-responsive systems, and surface-functionalized carriers have shown promise in overcoming these limitations. Prodrug-based systems have significantly advanced the field of drug delivery by enabling targeted and controlled therapeutic interventions. However, optimization of prodrug activation mechanisms and mitigation of undesired off-target effects remain ongoing challenges. Advances in prodrug design are increasingly supported by technologies such as computationally guided molecular optimization, microfluidic platforms for high-throughput screening, and the development of biomaterials with stimulus-responsive functionalities, all of which are anticipated to play a significant role in shaping the next generation of prodrug-based delivery system. Future research should focus on translational approaches that bridge laboratory success with clinical applicability.