Several variants of hybrid polyelectrolyte microcapsules (hPEMC) were designed and produced by modifying in situ gelation methods and layer-by-layer (LbL) techniques. All of the hPEMC designs tested in the study demonstrated high efficiency of the model hydrophilic compound loading into the carrier cavity. In addition, the microcarriers were characterized by high efficiency of incorporating the model hydrophobic compound rhodamine B isothiocyanate (RBITC) into the hydrophobic layer consisting of poly-(d,l)-lactide-co-glycolide (PLGA), oligo-(l)-lactide (OLL), oligo-(d)-lactide (OLD) and chitosan/gelatin/poly-l-lactide copolymer (CGP). The obtained microcapsules exhibited high storage stability regardless of the composition and thickness of the polyelectrolyte shell. Study of the impact of hybrid polyelectrolyte microcapsules on viability of the adhesive L929 and suspension HL-60 cell lines revealed no apparent toxic effects of hPEMC of different architecture on live cells. Interaction of hPEMC with peritoneal macrophages for the course of 48 h resulted in partial deformation and degradation of microcapsules accompanied by release of the content of their hydrophilic (BSA-fluorescein isothiocyanate conjugate (BSA-FITC)) and hydrophobic (RBITC) layer. Our results demonstrate the functional efficiency of novel hybrid microcarriers and their potential for joint delivery of drugs with different physico-chemical properties in complex therapy.