Engineering Nanotherapeutics Through Interfacial Mechanics: Mechanobiology and Precision Drug Delivery.

The biological microenvironment is inherently mechanical, with cells continuously sensing and responding to fluid shear stress, matrix stiffness, tensile strain, hydrostatic pressure, and other physical cues through highly conserved mechanotransduction pathways. These mechanical interactions arise across biological interfaces and are increasingly investigated using microfluidic and nanofluidic technologies that enable precise control of physiologically relevant mechanical environments. While nanomedicine has traditionally focused on biochemical targeting and molecular recognition, growing evidence demonstrates that interfacial mechanical forces critically regulate nanoparticle transport, vascular adhesion, cellular uptake, biodistribution, therapeutic activation, and treatment efficacy. Simultaneously, pathological alterations in tissue mechanics have emerged as hallmarks of numerous diseases, including cancer, cardiovascular disease, fibrosis, pulmonary hypertension, neurodegeneration, and metabolic disorders, creating new opportunities for mechanics-guided therapeutic design. This Perspective develops an integrative framework in which interfacial mechanics is treated as an actionable engineering variable across the nanotherapeutic delivery pathway. The framework distinguishes three mechanistic roles of mechanics: as a determinant of therapeutic transport, as an activation signal for mechanically responsive materials, and as a biological target through mechanotransduction pathways. Particular attention is given to fluid shear stress, extracellular-matrix mechanics, strain, pressure, nano-cell interfacial interactions, and the use of microfluidic and nanofluidic systems to reproduce physiologically relevant mechanical environments. Experimentally demonstrated mechanically responsive systems are distinguished from prospective concepts, and the translational implications of mechanical heterogeneity, activation thresholds, off-target triggering, and combined mechanical-biochemical gating are examined. The Perspective further identifies quantitative and experimental requirements needed to advance mechanics-guided nanotherapeutics from conceptual designs toward predictive and clinically translatable systems. Collectively, this framework positions interfacial mechanics as a complementary design dimension to molecular targeting in precision drug delivery.