Programmed micromotors and nanomotors for active penetration of physiological barriers

Micro- and nanomotors (MNMs) represent a paradigm shift in active delivery systems, leveraging autonomous propulsion to overcome complex physiological barriers. A critical determinant of their success is structural programmability. This review systematically delineates how the nanoscale engineering of geometric asymmetry, surface bio-interfaces, and mechanical deformability governs the barrier-penetrating capabilities of MNMs. Rather than merely stating the importance of structure, we elucidate how programming these specific physicochemical attributes allows MNMs to efficiently convert diverse energy inputs (for example, enzymatic, magnetic, acoustic, and photothermal) into targeted local physical effects, such as localized shear stress, thermophoretic gradients, and cavitation forces. These programmable physical effects serve as the direct mechanisms for actively tearing through or navigating viscous mucus, high-shear vascular endothelia, dense tumor interstitium, and subcellular compartments. Furthermore, by evaluating comparative performance metrics across different structural designs and proposing prescriptive design principles, this review offers concrete mechanistic insights for engineering next-generation MNMs toward clinical translation.