Bio-integrated materials and devices can blur the interfaces between living and artificial systems. Microfluidics, bioelectronics, and engineered nanostructures, with close interactions with biology at the cellular or tissue levels, have already yielded a spectrum of new applications. Many new designs emerge, including of organ-on-a-chip systems, biodegradable implants, electroceutical devices, minimally invasive neuro-prosthetic tools, and soft robotics. In this review, we highlight a few recent advances of the fabrication and application of smart bio-hybrid systems, with a particular emphasis on the three-dimensional (3D) bio-integrated devices that mimic the 3D feature of tissue scaffolds. Moreover, neurons integrated with engineered nanostructures for wireless neuromodulation and dynamic neural output are briefly discussed. We also discuss the progress in the construction of cell-enabled soft robotics, where a tight coupling of the synthetic and biological parts is crucial for efficient function. Finally, we summarize the approaches for enhancing bio-integration with biomimetic microand nanostructures.