Repurposing Non-oncologic Drugs via Targeted Nanocarriers for Cancer Therapy: Mechanisms, Synergistic Combinations, and Clinical Translation.

The urgent need for innovative cancer therapies has driven increasing interest in repurposing drugs originally developed for non-oncological diseases. Several FDA-approved and clinically investigated agents, including mesalamine, celecoxib, gliclazide, metformin, itraconazole, and doxycycline, have shown anticancer potential through diverse mechanisms. However, despite their therapeutic potential, many of these drugs suffer from limited tumor selectivity, suboptimal bioavailability, and off-target toxicity when used in oncology. Nanocarrier-based delivery systems offer a promising strategy to address these limitations by improving drug solubility, enhancing tumor accumulation, and enabling more selective delivery to cancer cells and the tumor microenvironment. In this context, nanocarriers not only serve as delivery vehicles but also provide opportunities for controlled release, combination therapy, and stimulus-responsive treatment strategies. This review summarizes recent progress in repurposing non-oncologic drugs for cancer therapy with a particular focus on nanocarrier-enabled delivery approaches. We discuss the molecular mechanisms underlying the anticancer activity of repurposed drugs, as well as their targeting of tumor cells, the tumor microenvironment, and cancer stem cells. In addition, we highlight advances in integrating these agents into nanocarrier platforms for combination therapy, photodynamic therapy, dual-drug delivery, and stimuli-responsive systems. Finally, we address translational challenges, including regulatory and intellectual property considerations, and discuss future perspectives involving artificial intelligence and personalized medicine to accelerate clinical implementation.