Abstract: Solar prominences are formed by partially ionized plasma with inter-particle collision frequencies generally warranting magnetohydrodynamic treatment. In this work, we explore the dynamical impacts and observable signatures of two-fluid effects in the parameter regimes when ion-neutral collisions do not fully couple the neutral and charged fluids. We perform 2.5D two-fluid (charges - neutrals) simulations of the Rayleigh-Taylor instability (RTI) at a smoothly changing interface between a solar prominence thread and the corona. The purpose of this study is to deepen our understanding of the RTI and the effects of the partial ionization on the development of RTI using non-linear two-fluid numerical simulations. Our two-fluid model takes into account viscosity, thermal conductivity, and collisional interaction between neutrals and charges: ionization/recombination, energy and momentum transfer, and frictional heating. We explore the sensitivity of the RTI dynamics to the prominence equilibrium configuration, including the impact of the magnetic field strength and shear supporting the prominence thread, and the amount of prominence mass-loading. We show that, at small scales, a realistically smooth prominence-corona interface leads to qualitatively different linear RTI evolution than that expected for a discontinuous interface, while magnetic field shear has the stabilizing effect of reducing the growth rate or eliminating the instability. In the non-linear phase, we observe that in the presence of field shear the development of the instability leads to formation of coherent and interacting 2.5D magnetic structures, which, in turn, can lead to substantial plasma flow across magnetic field lines and associated decoupling of the fluid velocities of charges and neutrals.