A composition (and associated methods) including a plurality of treated red blood cells for simulating reticulocytes, and particularly an immature reticulocyte fraction, of whole blood when processed as a sample in an automated analyzer capable of detecting reticulocytes. A method for making the composition or other simulated reticuolcyte may include steps of contacting a suspension of a plurality of red blood cells each having a membrane in an initial state that surrounds an interior volume of a cell with an effective amount of a hypertonic permeabilizing solution including dimethyl sulfoxide and a hypotonic loading agent delivery solution including a loading agent, for a sufficient time to form a plurality of pores in the membrane, for permitting the loading agent to enter into the interior volume of the cells, and, after entry of a desired amount of the loading agent into the interior volume of the cell, for sealing the pores for substantially restoring the membrane to the initial state while substantially encapsulating the loading agent within the resulting cell, and preferably also retaining within the resulting cell a substantial amount of hemoglobin from the original starting red blood cell.