Chrono-modulated drug delivery systems for oncology: Mechanisms, translational evidence, and pharmaceutical innovations

Conventional chemotherapy is limited by severe systemic toxicity, suboptimal pharmacokinetics, and nonspecific drug distribution. Chrono-modulated drug delivery systems (CDDS) address these challenges by aligning drug release with circadian rhythms, thereby enhancing efficacy and minimizing adverse effects. This strategy capitalizes on temporal fluctuations in drug metabolism, DNA repair mechanisms, cell proliferation, and immune function to refine pharmacokinetic and pharmacodynamic profiles. This review synthesizes recent preclinical and emerging clinical studies exploring chronomodulated chemotherapy, with a focus on delivery-system design and translational feasibility. Technological innovations, including stimuli-responsive hydrogels, nano- and micro-carriers, 3D printed formulations, and programmable infusion devices, enable precise temporal drug release. Comparative evaluation of these platforms reveals improved therapeutic indices and reduced toxicity, underscoring the clinical promise of chronotherapy in oncology. However, significant obstacles remain, including limited clinical standardization, regulatory barriers for drug-device combinations, formulation complexity, and inter-patient chronotype variability. Future integration of wearable biosensors, AI, and adaptive trials is expected to accelerate clinical translation. Overall, this review positions chronomodulated drug delivery as a strategically mature yet clinically underutilized approach for advancing precision oncology.