In this work, we theoretically investigate the implications of nonlinear electrophoretic effects on the transport and size-based separation of charged macromolecules in nanoscale confinements. By employing a regular perturbation analysis, we address certain nontrivial features of interconnection among wall-induced transverse migrative fluxes, electrophoretic and electroosmotic transport, confinement-induced hindered diffusive effects, and hydrodynamic interactions in detail. We demonstrate that there occurs an optimal regime of influence of the nonlinear electrophoretic effects, within which high values of separation resolution may be achieved. This size-based optimal regime, however, can be effectively exploited only for nanochannel flows, as attributed to the strong electric double layer interactions prevalent within the same.