Engineering combination nanomedicines to overcome cancer resistance

Combination nanomedicine enables the coordinated delivery of multiple therapeutic agents using engineered nanosystems to address tumor heterogeneity, multidrug resistance, and systemic toxicity. Despite extensive preclinical progress, many combination nanomedicine strategies fail to translate clinically due to poor pharmacokinetic coordination, limited predictive models, and manufacturing constraints. This review examines design principles for co-delivery platforms based on liposomal, polymeric, inorganic, hybrid, and biomimetic carriers, with attention to pharmacokinetics, biodistribution, endosomal escape, and interactions with the tumor microenvironment. Strategies integrating chemotherapy, immunotherapy, gene- and RNA-based therapies, photodynamic and photothermal modalities, and selected natural compounds are summarized to achieve synergistic therapeutic effects. Stimuli-responsive and actively targeted systems are highlighted for precise release and improved tumor accumulation. Translational progress from preclinical studies to clinical experience, including opportunities and constraints related to manufacturing reproducibility, quality control, immunogenicity, and long-term fate were discussed. Overall, combination nanomedicine shows promise for improving efficacy and safety in cancer therapy, and future work should prioritize modular, clinically scalable platforms, standardized characterization, clinically relevant models, and pathways for scalable production and regulatory evaluation.