Nanomedicine Strategies for Targeting Tumor Metabolic Vulnerabilities

Abstract Tumor metabolic reprogramming contributes to tumor development and therapeutic resistance and is characterized by alterations in glucose, amino acid, lipid, and mitochondrial metabolism that collectively support tumor proliferation, survival, and phenotypic plasticity. Despite encouraging preclinical results for metabolic pathway inhibitors, their clinical application is constrained by systemic toxicity, metabolic heterogeneity, adaptive metabolic plasticity, and limited patient stratification. Tumor metabolic vulnerabilities arise from context-specific metabolic dependencies shaped by genetic alterations, cellular states and microenvironmental pressures, which offer opportunities for selective therapeutic targeting. Nanomedicine provides a flexible platform for exploiting these vulnerabilities, and preclinical studies have demonstrated the potential benefits of improved pharmacokinetic properties, enhanced tumor accumulation, and controlled or combinatorial therapeutic delivery. However, whether these advantages translate into improved clinical outcomes remains dependent on the tumor biology, delivery efficiency, safety, and patient selection. Apart from being drug carriers, nanoplatforms may regulate therapeutic action in space and time, facilitating synergistic metabolic interventions and supporting emerging precision strategies such as adaptive treatment and response-guided optimization. This review discusses the mechanistic origins of tumor metabolic abnormalities and their therapeutic implications, followed by nanomedicine strategies targeting major metabolic vulnerabilities. We further summarize the system-level nanomedicine approaches aimed at overcoming therapeutic resistance and addressing metastasis, immunosuppressive microenvironments, and metabolic plasticity.