Nano-bio interactions are size-dependent. The present study investigates whether core–shell chitosan-alginate particle size governs biological activities as well as protein release profile. A coaxial electrospraying was used to fabricate bovine serum albumin (BSA)-loaded core–shell micro/nanoparticles and were fully characterized. The bio/hemocompatibility of the particles was assessed using MTT and hemolytic assays, respectively, followed by the uptake assessment using flow cytometry. Finally, protein absorption was investigated using SDS-PAGE. The SEM size of the microparticles, the hydrodynamic, and the actual sizes of the nanoparticles were 1.2 μm, 90.49 nm, and 50 nm, respectively. Interactions among two polymers and BSA were observed using DSC analysis. BET analysis showed a more surface area for nanoparticles. A sustained release trend of BSA was observed after 14- and 10-day for microparticles and nanoparticles, respectively. Microparticles exhibited excellent hemocompatibility (< 5% hemolysis) and cell viability (at least > 70%) in all concentrations. However, acceptable hemolytic activity and cell viability were observed for nanoparticles in concentrations below 250 μg/mL. Furthermore, nanoparticles showed greater cellular uptake (~ 4 folds) and protein absorption (~ 1.61 folds) than microparticles. Overall, the developed core–shell chitosan-alginate particles in the micro/nanoscale can be promising candidates for biomedical application and regenerative medicine regarding their effects on above mentioned biological activities.