The regeneration of enzymatic cofactors by cell‐free synthetic modules is a key step towards producing a purely synthetic cell. Herein, we demonstrate the regeneration of the enzyme cofactor NAD+ by photo‐oxidation of NADH under visible‐light irradiation by using metal‐free conjugated polymer nanoparticles. Encapsulation of the light‐active nanoparticles in the lumen of polymeric vesicles produced a fully organic module able to regenerate NAD+ in an enzyme‐free system. The polymer compartment conferred physical and chemical autonomy to the module, allowing the regeneration of NAD+ to occur efficiently, even in harsh chemical environments. Moreover, we show that regeneration of NAD+ by the photocatalyst nanoparticles can oxidize a model substrate, in conjunction with the enzyme glycerol dehydrogenase. To ensure the longevity of the enzyme, we immobilized it within a protective silica matrix; this yielded enzymatic silica nanoparticles with enhanced long‐term performance and compatibility with the NAD+‐regeneration system.