Bioorthogonal catalysis mediated by transition metal catalysts (TMCs) provides controlled in situ activation of prodrugs through chemical reactions that do not interfere with cellular bioprocesses. The direct use of 'naked' TMCs in biological environments can have issues of solubility, deactivation, and toxicity. Here, we demonstrate the design and application of a biodegradable nanoemulsion-based scaffold stabilized by a cationic polymer that encapsulates a palladium-based TMC, generating bioorthogonal nanocatalyst "polyzymes". These nanocatalysts enhance the stability and catalytic activity of the TMCs while maintaining excellent mammalian cell biocompatibility. The therapeutic potential of these nanocatalysts was demonstrated through efficient activation of a non-toxic prodrug into an active chemotherapeutic drug, leading to efficient killing of cancer cells.