Reactive sulfur species (RSS) are a family of crucial biosignals for regulating cell processes. Among these, hydrogen polysulfide (H2 Sn , n ≥ 2) is a hallmark of tumor suppressor activation and regarded as the actual regulator to mediate sulfur-related biology. However, high effective recognition of intracellular H2 Sn is insurmountable due to its extremely low concentration and the disturbance of RSS analogues. Here an H2 Sn -responsive macromolecule that can distinguish H2 Sn from intracellular RSS through polymer degradation in ultrasensitive and highly selective manner is reported. This kind of polymers can further self-assemble into vesicular nanostructure. Upon cell uptake, they can be function as "all-in-one" H2 Sn -nanoplatforms, in order to fulfill multiple ambitious tasks including monitoring the H2 Sn biosynthetic pathways, unraveling the puzzles of H2 Sn -mediated cellular events, and conducting H2 Sn pathological milieu-specific drug delivery.