Hybrid and multicompartment carriers are of significant interest for the development of next-generation therapeutic drug carriers. Herein, fundamental investigations on layer-by-layer (LbL) capsules consisting of two different polymers are presented. The hybrid systems were designed to have pH-responsive, charge-shifting poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) inner layers and low-fouling poly(N-vinylpyrrolidone) (PVPON) outer layers. Planar hybrid films with different layer ratios were studied by quartz crystal microgravimetry (QCM) and atomic force microscopy (AFM). The information obtained was translated to particulate templates to prepare hybrid capsules, which were stabilized by click chemistry. The charge-shifting behavior of PDPA improved the cargo encapsulation and initial retention of a model CpG cargo, while outer layers of PVPON improved biofouling properties compared to single-component PDPA capsules. The results demonstrate the need to understand and design multifunctional systems that can successfully embody different functionalities in a single, stable construct for the fabrication of next-generation drug and gene delivery carriers aimed at overcoming the challenges encountered in biological systems.