Bioorthogonal catalysis mediated by abiotic transition metal catalysts (TMCs) is emerging as a momentum-gathering strategy for in situ generation of therapeutics. However, the unpredictable leakage and deposition of TMCs in living systems easily lead to nonspecific exposure of catalysts and concomitant off-target prodrug activation. Herein, we propose an enzyme-gated bioorthogonal catalytic nanoreactor constructed from hyaluronic acid (HA)-coated dendritic mesoporous silica nanoparticles (DMSNs), where the latter serves as a host for robustly immobilizing organometallic Ru(II) catalysts via covalent interactions. The covalent immobilization of catalysts within the nanoscaffold effectively avoids nonspecific metal leakage under biological conditions. Importantly, the grafted HA not only acts as a "gatekeeper" preventing unintended catalyst exposure in nontargeted tissues but also acts as a ligand targeting CD44 overexpressed cancer cells. Upon receptor-mediated endocytosis into tumor cells, HA is degraded by the overexpressed hyaluronidase-1, leading to the channel opening of the nanoreactors and hence gaining the accessibility of Ru(II) complexes to prodrugs. The therapeutic potency of this enzyme-gated nanoreactor in mediating site-specific activation of caged prodrugs was systematically demonstrated both in cellular settings and in tumor-bearing murine models. This enzyme-gated strategy enhances the efficacy of localized treatment while avoiding off-target prodrug activation, paving the way for advancing bioorthogonal catalysis for disease management in a safe and effective way.