<p>Osmotic pressure (OP) is widely recognized as a crucial driving force for the flow of body fluids. To provide a reasonable explanation for osmosis-dependent pathophysiological phenomena in live cells, we establish fluorescence resonance energy transfer (FRET)-based intermediate filament (IF) tension probes, converting the osmotic effect into optical signals. We then propose the theory of bio-osmotic pressure (bio-OP), which relies on the selective permeability of ion channels and water flux. Protein nanoparticles (PNs) play a crucial role in modulating the transmembrane osmotic gradient by regulating the electrical activity of the plasma membrane and voltage-dependent ion channels. Different ion compositions exhibit synergistic or antagonistic effects on PN-induced electrical activity. As a result, PNs are crucial for maintaining the intracellular osmotic effect. PNs, in collaboration with changes in ions and water, establish a new homeostasis in membrane potential and bio-OP. This collaboration led to the synergistic regulation of electromechanical activity involved in the occurrence and development of various diseases associated with bio-OP, such as brain edema. Elucidation of the mechanism underlying bio-OP can provide a novel viewpoint on the pathophysiology of various complex diseases. Hence, further research on bio-OP needs to be conducted.</p>