Tumor microenvironment-specific nanomedicine: from biology-driven to multi-omics-guided precision engineering

The tumor microenvironment (TME) is a structurally and functionally heterogeneous ecosystem in which extracellular matrix (ECM) remodeling, vascular-lymphatic dysfunction, hypoxia, acidosis, and spatially organized immunosuppressive networks jointly constrain nanoparticle accessibility, intratumoral distribution, and therapeutic efficacy. Conventional nanomedicine strategies based on passive accumulation, ligand-mediated targeting, and stimulus-responsive release have produced important advances, but they remain limited by empirical design principles that often overlook interpatient and intratumoral heterogeneity. Recent advances in single-cell profiling, spatial transcriptomics (ST), and complementary multi-omics technologies have revealed that the TME comprises regionally distinct stromal architectures, endothelial states, metabolic niches, proteolytic landscapes, and immune-stromal interaction networks. These datasets provide an opportunity to move beyond tumor-averaged descriptors by identifying cell-type-specific receptors, stromal and vascular barriers, spatially restricted release cues, and immune-excluded niches that govern nanoparticle transport, activation, and therapeutic response. In this review, we first summarize key TME barriers relevant to nanomedicine delivery, including ECM architecture, vascular pathophysiology, hypoxia, acidosis, and tumor immune microenvironment (TIME) dynamics. We then propose a closed-loop omics-to-design framework that translates spatially resolved biological features into actionable nanoparticle engineering parameters, including ligand selection, stromal-penetrating and barrier-modulating architectures, subtype-informed vascular delivery, and omics-defined responsive release strategies. Finally, we discuss the translational requirements for implementing this paradigm, including patient stratification, companion diagnostic development, chemistry, manufacturing, and controls (CMC) considerations, regulatory pathways, and the practical shift from fully personalized formulations toward stratification-matched libraries of pre-validated nanomedicines. By combining TME biology, spatial multi-omics, functional engineering, and translational planning, this review outlines an integrated strategy for next-generation precision nanomedicine designed to overcome tumor heterogeneity and enhance therapeutic efficacy.