Silicon-based materials and devices represent a unique platform for interrogating fundamental biophysical processes. Recent advances in device designs and fabrications have enabled a wide variety of new silicon-based electronic and optoelectronic systems, which display multi-functional modalities that could be exploited for interfacing with various biological organizations. Besides the top-down fabrication which involves conventional lithographical processes, the bottom-up synthesis represents an alternative yet equally important method for the construction of silicon structures. In particular, the geometry and composition of the final construct can be tuned precisely during the materials growth, promising novel functions or applications beyond those offered by traditional platforms. In this thesis, I will report the design of a spectrum of silicon structures for the enhanced mechanical, electrical, and thermal biointerfaces, with targets spanning multiple length scales from nanoscopic organelles, microscopic single cells up to macroscopic tissues or organs. I will also focus on the study of fundamental aspects during the bottom-up synthesis to elucidate the underlying physicochemical processes that shape the silicon structures and properties. First, I will introduce a biocompatible and degradable mesostructured form of amorphous silicon with multiscale structural and chemical heterogeneities. I will also show that the heterogeneous silicon mesostructures can be used to design a lipid-bilayer-supported bioelectric interface that is remotely controlled and temporally transient, and that permits non-genetic and subcellular optical modulation of the electrophysiology dynamics in single dorsal root ganglia neurons. Secondly, I will demonstrate a biology-guided rational design principle for establishing intra-, inter- and extracellular silicon-based interfaces, where silicon and biological targets have matched properties. I will then demonstrate the utility of these interfaces by showing light-controlled non-genetic modulations of intracellular calcium dynamics, cytoskeleton-based transport and structures, cellular excitability, neural transmitter release from brain slices, and brain activities in vivo. Then, I will demonstrate an atomic-gold enabled three-dimensional (3-D) lithography for silicon mesostructures, by showing one example where iterated deposition-diffusion-incorporation of gold over silicon nanowires can produce mesostructured silicon spicules. In addition, I will show the anisotropic spicule has a strong interfacial interaction with the extracellular matrix, suggesting enhanced mechanical biointegrations. Finally, I will demonstrate that a liquid gold-silicon alloy established in classical vapor-liquid-solid growth can deposit ordered and three-dimensional rings of isolated gold atoms over silicon nanowire sidewalls. I will show that the single atomic gold-catalyzed chemical etching of silicon can lead to massive and ordered 3-D grooves on Si surfaces, which can serve as self-labelled and ex situ markers to resolve several complex silicon growths.