Infections associated with bacterial adhesion and subsequent biofilm formation constitute a grave medical issue for which conventional antibiotic therapies remain ineffective. Here, we introduce a new strategy employing nanotechnology to create smart surfaces with self-defending properties that result in controlled drug production and controlled release for long periods of time. Self-defending surfaces on solid supports are prepared by immobilizing polymer nanoreactors containing an encapsulated biocatalyst that can convert non-antibiotic substrates to an abiotic drug. For medical applications and biosensing, the immobilization method must fulfill specific criteria, and these were achieved by an immobilization strategy based on Schiff base formation between aldehyde groups on the outer surface of nanoreactors and amino groups on the solid support surface, followed by reductive amination. The resulting self-defending surfaces allow control of drug production at a specific rate for a specific period of time by adding predetermined amounts of substrate to the outer medium, minimization of dosages and therefore systemic toxicity, and limitation of the immune response. Such self-defending surfaces producing drugs offer a versatile strategy for the development of smart surfaces with improved stability and efficacy (by changing the biocatalyst) to serve as biosensors, antifouling surfaces, or smart packages.