Surface-enhanced　Raman　scattering　(SERS)　is　a　super-sensitive　analysis　technology　based　on　the　target　molecular　fingerprint　information.　The　enhancement　of　local　electromagnetic　field　of　the　SERS　substrate　would　increase　the　target　molecules＇　Raman　intensity　which　adsorb　on　the　surface　of　nanoparticles.　However,　the　existing　adhesive　macromolecules　in　the　complex　mixed　sample　would　interfere　with　the　adsorption　of　small　target　molecules,　and　it　weakens　the　Raman　intensity　of　target　molecules.　Microgels　are　one　of　the　potential　materials　to　suppress　the　interference　of　adhesive　macromolecules　and　to　avoid　the　complex　pretreatments.　However,　most　of　the　current　microgel　synthesis　methods　involve　complex　operations　with　precise　instrumentation　or　the　interference　of　oil　and　organic　reagents.　In　this　work,　a　simple　and　oil-free　method　was　proposed　to　synthesize　the　gold　nanobipyramid　(Au　NBP)@Ag@hyaluronic　acid　microgel　via　the　condensation　reaction　of　carboxyl　and　amino　groups.　As　a　proof-of-concept　demonstration　for　small-molecule　detection,　the　rhodamine　6G　(R6G)　molecules　were　allowed　to　enter　inside　the　microgel　through　the　meshes　and　adsorb　on　the　surface　of　Au　NBP@Ag　nanoparticles　within　30　min,　while　the　macromolecule　(bovine　serum　albumin　in　this　case)　was　retained　outside　the　microgel　in　the　meantime.　In　addition,　under　the　combined　action　of　lightning　rod　effect　of　Au　NBP　and　surface　plasmon　resonance　effect　of　silver　render　the　microgels　with　high　SERS　activity.　The　synthetic　Au　NBP@Ag@hyaluronic　acid　microgels　were　applied　to　detect　6-thioguanine　in　the　human　serum　without　any　pretreatment　process,　and　it　showed　a　high　signal　enhancement　and　stable　SERS　signal,　which　can　satisfy　the　requirement　of　clinical　diagnosis.　These　results　show　that　the　proposed　microgels　have　potential　applications　in　the　field　of　point-of-care　testing.　©　2021　American　Chemical　Society.