Engineering stem cell morphology and tissue architecture through nano-engineered materials

Nano-engineered approaches are commonly used to guide stem cell behavior in regenerative systems, yet achieving consistent tissue-level function remains difficult. The current review argues that tissue architecture is a primary contributor to both tissue function and their interplay, rather than merely a secondary outcome of nanoscale regulation. This review synthesizes primary experimental results using an architecture-first paradigm to investigate the effects of nanoscale signals on multicellular organization and functional performance. Nanomaterials can influence cellular adhesion and ligand organization, shape nuclear architecture and polarity, and constrain higher-order organization at the single-cell level. The review identifies nano-biointerface-mediated intercellular coordination as the primary mechanism via which local nanoscale signals synchronize adjacent cells, enabling coherent multicellular formations. In engineered three-dimensional tissue environments, nano-biointerface-driven cell coordination enables tissue-scale organization beyond what cellular phenotype alone can predict. Functional validation across excitable and contractile tissues demonstrates that electrical conduction and mechanical force transmission depend on architectural coherence rather than marker expression or intrinsic single-cell properties. Nano-engineered materials displaying suitable differentiation profiles but lacking spatial continuity or coordination consistently fail to achieve robust function, identifying architecture as the key limiting factor for achieving robust tissue function. Nano-engineering is thus viewed not as a final solution but as a method for exploring the relationship between structure and function in tissue morphogenesis, providing a cohesive framework for function-based tissue engineering. Finally, current limitations, including inadequate quantitative descriptors, are critically evaluated, revealing research gaps and future directions toward functionally predictive tissue architectures.