Enzyme‐responsive and biocompatible supramolecular nanocarriers (NCs) have attracted intensive attention in the field of biomaterials, and have found many feasible applications, particularly for controlling drug‐release at specific anchor sites where the enzyme is overexpressed. However, the introduction of specific enzyme‐responsive sites in drug nanocarriers that can be enzymatically triggered to release drugs within tumor cells remains a challenge. In this manuscript, an enzyme‐responsive supramolecular nanoparticle, (SBE)7m‐β‐CD ⊃ PS NPs is successfully prepared, based on inducing aggregation of negatively charged cyclodextrin toward positively charged protein. The obtained nanoparticles showed trypsin‐trigger disassemble behavior that is considered as drug vehicles to load antitumor drug celastrol (CSL). Furthermore, CSL‐loaded NPs exhibit controlled release behavior of CSL in response to trypsin (TPS) stimulation. Notably, cell biology experiments reveal that loading CSL by (SBE)7m‐β‐CD ⊃ PS NPs not only reduces cytotoxicity for normal cells but also presents a similar therapeutic effect of free CSL for five tumor cells. The obtained nanoparticle appears to hold practical potential for the controllable release of CSL in tumor cells.

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HA/(MI)7-β-CD NCs exhibits HA receptor-mediated targeting and disassembly properties under HAase stimulation, which was utilized to trap, targeted deliver and controlled release of anti-liver cancer compound CSL.