Physicochemical design of nanobiomaterials in oncology: structure-to-function principles for sequential transport and delivery

The physicochemical properties of nanobiomaterials (NBM) have enabled nanomedicine platforms capable of addressing major therapeutic challenges in oncology, including poor bioavailability, systemic toxicity, limited tumor accumulation, and off-target effects. Through coordinated optimization of size, shape, and surface chemistry, NBM support controlled drug release, improved targeting strategies, and modulation of the tumor microenvironment (TME). This structure-to-function tuning further governs their interaction with biological transport barriers, enabling navigation across abnormal vasculature, dense extracellular matrix, and elevated interstitial fluid pressure. This review critically examines key physicochemical properties (size, shape, and surface chemistry) that govern nano-bio interactions and influence circulation, cellular uptake, biodistribution, immune evasion, and intracellular transport in solid tumors. Emphasis is placed on structure-to-function relationships that link material design with therapeutic performance. The integration of physicochemical optimization with the distinct transport phenotypes of TME highlights that effective NBM require coordinated tuning of multiple parameters rather than merely design adjustments. The synergistic modulation of physicochemical properties can produce adaptive, multifunctional NBM capable of engaging specific TME components and overcoming critical barriers. Together, these insights establish the foundation for rational NBM engineering and provide the mechanistic basis for tumor phenotype focused strategies.