Aligning organ-specific toxicities with formulation strategies: a rational design approach to chemotherapy optimization.

Chemotherapy-induced toxicity remains a persistent challenge in oncology, where multi-organ injury continues to limit clinical outcomes despite decades of drug optimization and formulation innovation. Although mechanistic studies have elucidated key pathways of damage, current formulation strategies often overlook organ-specific pathophysiology, resulting in nonspecific mitigation approaches. This review fills a methodological gap by introducing a toxicity-informed framework that integrates organ-specific injury mechanisms with formulation design principles to support rational chemotherapy optimization. By analyzing toxicities in key organs with delivery system advances-including nanocarriers, prodrug designs, and stimuli-responsive platforms-we construct a decision-making flowchart to guide rational formulation selection based on toxicity profiles. Representative new drugs such as Padcev® and Zepzelca® are examined to highlight how discordance between toxicity mechanism and delivery design leads to avoidable adverse effects. This framework bridges mechanistic toxicology with formulation logic, aiming to facilitate more targeted, organ-aware chemotherapeutic design. In this review, we synthesize over 240 publications published up to June 2025, we consolidate current evidence into a unified decision-making model that aligns toxicity mechanisms with formulation strategies. This effort lays a foundation for future integration of mechanism-based formulation frameworks into more systematic and predictive models for chemotherapeutic design and clinical translation.