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.　©　The　Author(s)　2025.