Microstructured　optical　fibers　(MOFs)　provide　solutions　for　breaking　through　the　bottlenecks　in　areas　of　high-power　transmission　and　high-efficiency　optical　waveguides.　Other　than　transporting　light　waves,　MOFs　can　synergistically　combine　microfluidics　and　optics　in　a　single　fiber　with　an　unprecedented　light　path　length　not　readily　achievable　by　planar　optofluidic　configurations.　Here,　we　demonstrate　that　hollow-core　anti-resonant　optical　fibers　(HcARFs)　can　significantly　enhance　Raman　scattering　by　over　three　orders　of　magnitude　(EF　approximate　to　5000)　compared　with　a　planar　setup,　due　to　the　joint　mechanisms　of　strong　light-matter　interaction　in　the　fiber　core　and　the　cumulative　effect　of　the　fiber.　The　giant　enhancement　enables　us　to　develop　the　first　optical　fiber　sensor　to　achieve　single　cancer　exosome　detection　via　a　sandwich-structured　strategy.　This　enables　a　multiplexed　analysis　of　surface　proteins　of　exosome　samples,　potentially　allowing　an　accurate　identification　of　the　cellular　origin　of　exosomes　for　cancer　diagnosis.　Our　findings　could　expand　the　applications　of　HcARF　in　many　exciting　areas　beyond　the　waveguide.