Materials that employ microstructure features to manage radiation damage and maintain high-temperature mechanical properties are especially desirable for improving the safety and efficiency of advanced nuclear reactors. High crystallization temperature amorphous ceramics and nickel-based alloys are very promising candidates but have some challenging issues. Amorphous ceramics exhibit ‘brittle-like’ behavior though they exhibit superior thermo-mechanical properties and structural stability at high temperatures and under irradiation. We propose to manipulate microstructures of amorphous ceramics via self-patterning amorphous Ni-rich ceramic nanoclusters (referred to as amorphous ceramic composites, ACCs) to improve the ductility of amorphous ceramics while retaining their superior thermo-mechanical properties. Nickel alloys are used in Molten Salt Reactors but sufficient irradiation resistance, improved helium management, elevated-temperature strength, and the resistance to neutron irradiation-induced loss of creep ductility are urgently demanded. We propose to self-pattern nanosized, thermally stable, radiation-tolerant amorphous ceramic particles in nickel alloys (referred to as amorphous ceramic reinforced metallic alloys, ACMs) in order to trap and manage helium and irradiation-induced defects at the matrix-particle interfaces, and retain high-temperature strength by dislocation-particles interactions in addition to solid solution strengthening. In this lecture, we demonstrate our hypothesis with Ni-SiOC ACCs and SiOC-Ni ACMs as a function of constituent fraction and microstructure, assess their mechanical and irradiation properties, and discuss the effect of alloying elements on microstructure and mechanical properties of metal-amorphous ceramic nanocomposites.