A general approach is proposed to large-scale synthesize multi-stimuli-responsive bottlebrush-colloid Janus nanoparticles (JNPs) by preferentially tuning the composition of a single-chain nanoparticle (SCNP). The starting SCNP is achieved by electrostatic-mediated intramolecular crosslinking of poly(4-vinyl benzyl chloride)-b-poly(methacrylic acid) (PVBC-b-PMAA) in concentrated solution, and the metallic species is synchronously incorporated via coordination. By applying different metallic precursors and incorporating a free radical initiator to in situ induce the polymerization of vinyl monomers, the inorganic/organic compositions of the crosslinked colloid are broadly tunable. The PVBC tail can be further grafted with various polymer brushes through atom-transfer radical polymerization (ATRP). The magnetic-/pH-/thermo-responsive bottlebrush-colloid JNP of PVBC-g-PNIPAM-cPMAA@Co-PDMEAMA is derived, which shows excellent activity for emulsion interface manipulation and emulsion interfacial catalysis of hydrogenation reactions.