In recent experiments [T. Basta et al., Proc. Natl. Acad. Sci. U.S. A. 111, 670 (2014)] lipids and membrane proteins were observed to self-assemble into membrane protein polyhedral nanoparticles (MPPNs) with a well-defined polyhedral protein arrangement and characteristic size. We develop a model of MPPN self-assembly in which the preferred symmetry and size of MPPNs emerge from the interplay of protein-induced lipid bilayer deformations, topological defects in protein packing, and thermal effects. With all model parameters determined directly from experiments, our model correctly predicts the observed symmetry and size of MPPNs. Our model suggests how key lipid and protein properties can be modified to produce a range of MPPN symmetries and sizes in experiments. Utilization of MPPNs for high-resolution structural studies requires [4] control over the symmetry and size of MPPNs. In this Letter we develop a physical description of MPPNs which establishes a quantitative link between the shape of MPPNs and key molecular properties of their constituents. We first describe a simple meanfield model of MPPNs inspired by previous work on membrane budding [9-11] and viral capsid self-assembly [12]. Our mean-field model of MPPNs accounts for the lipid bilayer bending deformations induced by MscS [3,5,6] and the MscS packing defects resulting from the spherical topology of MPPNs, and yields the MPPN energy as a function of the number of MscS per MPPN without any free parameters. We confirm some of the key assumptions underlying our mean-field model by carrying out Monte Carlo simulations of a minimal molecular model of MPPN organization, which we formulate following previous work on viral capsid symmetry [13]. Finally, we use our mean-field model of MPPNs to calculate [12,14,15] the MPPN self-assembly phase diagram as a function of protein concentration, bilayer-protein contact angle, and protein size. We show that our model correctly predicts, with all model parameters determined directly from experiments, the observed [4] symmetry and size of MPPNs formed from MscS. Our results suggest that the preferred symmetry and size of MPPNs emerge from the interplay of protein-induced lipid bilayer deformations, topological defects in protein packing, and thermal effects.Mean-field model.-The membrane-spanning region of MscS [5,6] has an approximately conical shape [3,16] with radius ρ i ≈ 3.2 nm in the lipid bilayer midplane and bilayer-protein contact angle α ≈ 0.46-0.54 rad, yielding [3] protein-induced lipid bilayer bending deformations [see Fig. 1(b)]. The preferred MscS arrangement minimizing bilayer bending energy is expected [9-11] to be a uniform hexagonal lattice. Our simple mean-field model of MPPNs therefore considers, on the one hand, contri-