We report the synthesis of nanoparticle (NP) networks in a variety of sizes through the controlled cross linking reaction of ketone groups integrated into linear polyester backbones and a difunctionalized aminooxy ethylene cross-linker. In contrast to previous work forming nanonetworks from linear components with pendant reactive groups, the ketone functional group is part of the polymer backbone accomplished by copolymerization of 2-oxepane-1,5-dione (OPD) monomers together with S-valerolactone. This process precludes postpolymerization reactions, modifying pendant functional groups in the polyester component, and provides direct access to the cross-linking entity. Reactions with bis(aminooxy)poly(ethylene glycol) form networks in a rapidly proceeding process with linear precursors containing 4%, 8%, and 14% of OPD, in a ratio of two aminooxy groups per keto group. The concentration of the OPD unit in solution is another critical factor contributing to the controlled production of these particles as investigated in two conditions to yield a set of six particles in well-defined dimensions ranging from 39 to 173 nm. Ketoxime linkages are pH-responsive and provide an alternative faster degradation mechanism together with a hydrolysis of the polymer backbone. The reduction of the ketoxime linkages after nanoparticle formation resulted in an additional set of six particles in comparable sizes with stable alkoxyamine groups limiting the degradation to a slower hydrolysis. In this work, we prepared a series of twelve particles in a two- or three-step process starting from the synthesis of three different OPD-containing polymers and controlled cross-linking in two reaction concentrations, with or without reduction of the ketoxime connective group. These particles are promising drug delivery systems as a practical synthesis is combined with a tunable degradation leading to expanded options for drug release and is demonstrated in the release of the natural product Brefeldin A.