Prodrug Strategies in Atherosclerosis: Targeted Delivery and Therapeutic Advances.

Atherosclerosis is an advancing and complex vascular condition primarily associated with sustained inflammatory responses, oxidative imbalance, and disruptions in lipid homeostasis. These pathological features render it a major contributor to the global burden of cardiovascular disease, encompassing both morbidity and mortality. Traditional treatment modalities, including statins, angiotensin-converting enzyme inhibitors, PCSK9 inhibitors and surgical procedures, frequently encounter limitations due to inefficient pharmacokinetic profiles, insufficient targeting of pathological sites and widespread adverse effects. To address these therapeutic shortcomings, prodrug and nano-prodrug technologies have gained recognition as innovative systems capable of enabling site-specific and stimuli-activated therapeutic delivery in atherosclerotic disease management. This review discusses ROS-responsive prodrugs, biomimetic nano-prodrug platforms, and multifunctional theranostic nanotechnologies as alternative approaches for advanced atherosclerosis treatment. These systems enable targeted drug activation in oxidative plaque environments, improve pharmacokinetics, and enhance lesion-specific delivery via mechanisms such as VCAM-1 targeting, integrins, and cell membrane cloaking. Notably, in preclinical models nano-prodrugs have been reported to produce combined therapeutic effects by modulating lipid metabolism, reducing inflammation, and preventing foam cell formation, whereas theranostic platforms have enabled real-time monitoring of treatment response in animals. No nano-prodrug platform for atherosclerosis has yet been evaluated in humans. Despite progress, key barriers to clinical translation remain, including poor scalability and reproducibility of nanomaterials, patient variability in plaque biology, limited long-term safety data, and regulatory challenges for complex nanosystems. Future advances will require biomarker-guided patient selection, robust clinical validation, multistimuli-responsive designs, and well-defined regulatory standards. Overcoming these issues is vital for integrating nano-prodrug technologies into precision atherosclerosis therapy.